Selective androgen receptor modulators, analogs and derivatives thereof and uses thereof

ABSTRACT

This invention provides new compounds and uses thereof in treating a variety of diseases or conditions in a subject, including, inter alia, prostate cancer, muscle wasting diseases and/or disorders or a bone-related diseases and/or disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/831,880, filed Jul. 19, 2006 and U.S. Provisional ApplicationSer. No. 60/831,988, filed Jul. 19, 2006; both of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention provides nuclear hormone receptor binding compounds,compositions comprising the same and methods of use thereof in treatinga variety of diseases or conditions in a subject, including, inter alia,prostate cancer, muscle wasting and diseases or disorders relatedthereto, and/or or bone-related diseases or disorders.

BACKGROUND OF THE INVENTION

The nuclear hormone receptor superfamily is one of the largest classesof transcription factors and is involved in abundant physiologicalprocesses. The 48 members of this family are divided into three classeswith class 1 comprised of receptors for androgens (AR), estrogens (ER-αand ER-β), glucocorticoids (GR), progesterone (PR) andmineralocorticoids (MR). Class 2 contains receptors for retinoids,thyroids and vitamin D, while class 3 includes receptors for whichligands are yet to be identified (orphans). Nuclear hormone receptorshave an N-terminal domain (NTD) whose function is less characterized, aDNA binding domain (DBD) which is responsible for the binding ofreceptor to DNA response elements, a hinge region that contains thenuclear localization signal and a ligand binding domain (LBD) to whichligands bind and activate or inhibit receptor action. In addition, thereare two activation function domains, one in the NTD (AF-1) and the otherin the LBD (AF-2). Due to the high amino acid sequence homology of theDBD, moderate homology and similar secondary and tertiary structuralfeatures of the LBD, and common chemical features of steroidal ligands,class I receptors are often capable of binding (i.e., cross reacting)with the ligands of other class I receptors. For example, early studieswith AR and ER suggest that the orientation of the steroid in the LBD,with the steroid A-ring in contact with helix-3 and the D-ring incontact with helix-11 residues, is likely to be general for all thesteroid hormone receptors.

The androgen receptor (“AR”) is a ligand-activated transcriptionalregulatory protein that mediates induction of male sexual developmentand function through its activity with endogenous androgens. Androgensare generally known as the male sex hormones. The androgenic hormonesare steroids which are produced in the body by the testes and the cortexof the adrenal gland or can be synthesized in the laboratory. Androgenicsteroids play an important role in many physiologic processes, includingthe development and maintenance of male sexual characteristics such asmuscle and bone mass, prostate growth, spermatogenesis, and the malehair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857-75(1994)). The endogenous steroidal androgens include testosterone anddihydrotestosterone (“DHT”). Testosterone is the principal steroidsecreted by the testes and is the primary circulating androgen found inthe plasma of males. Testosterone is converted to DHT by the enzyme 5alpha-reductase in many peripheral tissues. DHT is thus thought to serveas the intracellular mediator for most androgen actions (Zhou, et al.,Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens includeesters of testosterone, such as the cypionate, propionate,phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, anddecanoate esters, and other synthetic androgens such as7-Methyl-Nortestosterone (“MENT”) and its acetate ester (Sundaram etal., “7 Alpha-Methyl-Nortestosterone(MENT): The Optimal Androgen ForMale Contraception,” Ann. Med., 25:199-205 (1993) (“Sundaram;”). Becausethe AR is involved in male sexual development and function, the AR is alikely target for effecting male contraception or other forms of hormonereplacement therapy.

The human progesterone receptor (PR) occurs as three different isoforms:PR-A, PR-B, and PR-C (Kastner et al., EMBO J. 9:1603-1614, 1990; Wei etal., Mol Endo 10:1379-1387, 1996), of which PR-A and PR-B are the mostabundant. However, the ratio of PR-A vs. PR-B isoforms is not constantamong target tissues, and this can alter the cellular response, becausethe activity of each isoform can vary.

There are very few compounds that exhibit partial progestin activityunder a wide variety of conditions. RU-486, the most commonly usedantiprogestin, displays partial agonist activity only under selectedconditions. Antiprogestin compounds with partial agonist activity areuseful for treating various progestin-regulated diseases and conditions,however, the few known antiprogestins have only limited partial agonistactivity, and there remains a need in the art for antiprogestins withbroad-range partial agonist activity.

Worldwide population growth and social awareness of family planning havestimulated a great deal of research in contraception. Contraception is adifficult subject under any circumstance. It is fraught with culturaland social stigma, religious implications, and, most certainly,significant health concerns. This situation is only exacerbated when thesubject focuses on male contraception. Despite the availability ofsuitable contraceptive devices, historically, society has looked towomen to be responsible for contraceptive decisions and theirconsequences. Although concern over sexually transmitted diseases hasmade men more aware of the need to develop safe and responsible sexualhabits, women still often bear the brunt of contraceptive choice. Womenhave a number of choices, from temporary mechanical devices such assponges and diaphragms to temporary chemical devices such asspermicides. Women also have at their disposal more permanent options,such as physical devices including IUDs and cervical caps as well asmore permanent chemical treatments such as birth control pills andsubcutaneous implants. However, to date, the only options available formen include the use of condoms and vasectomy. Condom use, however is notfavored by many men because of the reduced sexual sensitivity, theinterruption in sexual spontaneity, and the significant possibility ofpregnancy caused by breakage or misuse. Vasectomies are also notfavored. If more convenient methods of birth control were available tomen, particularly long-term methods which require no preparativeactivity immediately prior to a sexual act, such methods couldsignificantly increase the likelihood that men would take moreresponsibility for contraception.

Administration of the male sex steroids (e.g., testosterone and itsderivatives) has shown particular promise in this regard due to thecombined gonadotropin-suppressing and androgen-substituting propertiesof these compounds (Steinberger et al., “Effect of ChronicAdministration of Testosterone Enanthate on Sperm Production and PlasmaTestosterone, Follicle Stimulating Hormone, and Luteinizing HormoneLevels: A Preliminary Evaluation of a Possible Male Contraceptive,Fertility and Sterility 28:1320-28 (1977)). Chronic administration ofhigh doses of testosterone completely abolishes sperm production(azoospermia) or reduces it to a very low level (oligospermia). Thedegree of spermatogenic suppression necessary to produce infertility isnot precisely known. However, a recent report by the World HealthOrganization showed that weekly intramuscular injections of testosteroneenanthate result in azoospermia or severe oligospermia (i.e., less than3 million sperm per ml) and infertility in 98% of men receiving therapy(World Health Organization Task Force on Methods And Regulation of MaleFertility, “Contraceptive Efficacy of Testosterone-Induced Azoospermiaand Oligospermia in Normal Men,” Fertility and Sterility 65:821-29(1996)).

A variety of testosterone esters have been developed which are moreslowly absorbed after intramuscular injection and thus result in greaterandrogenic effect. Testosterone enanthate is the most widely used ofthese esters. While testosterone enanthate has been valuable in terms ofestablishing the feasibility of hormonal agents for male contraception,it has several drawbacks, including the need for weekly injections andthe presence of supraphysiologic peak levels of testosterone immediatelyfollowing intramuscular injection (Wu, “Effects of TestosteroneEnanthate in Normal Men: Experience From a Multicenter ContraceptiveEfficacy Study,” Fertility and Sterility 65:626-36 (1996)). Bone mineraldensity (BMD) decreases with age in both males and females. Decreasedamounts of bone mineral content (BMC) and BMD correlate with decreasedbone strength and predispose patients to fracture.

Osteoporosis is a systemic skeletal disease, characterized by low bonemass and deterioration of bone tissue, with a consequent increase inbone fragility and susceptibility to fracture. In the U.S., thecondition affects more than 25 million people and causes more than 1.3million fractures each year, including 500,000 spine, 250,000 hip and240,000 wrist fractures annually. Hip fractures are the most seriousconsequence of osteoporosis, with 5-20% of patients dying within oneyear, and over 50% of survivors being incapacitated. The elderly are atgreatest risk of osteoporosis, and the problem is therefore predicted toincrease significantly with the aging of the population. Worldwidefracture incidence is forecasted to increase three-fold over the next 60years, and one study estimated that there will be 4.5 million hipfractures worldwide in 2050.

Women are at greater risk of osteoporosis than men. Women experience asharp acceleration of bone loss during the five years followingmenopause. Other factors that increase the risk include smoking, alcoholabuse, a sedentary lifestyle and low calcium intake. However,osteoporosis also occurs frequently in males. It is well establishedthat the bone mineral density of males decrease with age. Decreasedamounts of bone mineral content and density correlates with decreasedbone strength, and predisposes to fracture. The molecular mechanismsunderlying the pleiotropic effects of sex-hormones in non-reproductivetissues are only beginning to be understood, but it is clear thatphysiologic concentrations of androgens and estrogens play an importantrole in maintaining bone homeostasis throughout the life-cycle.Consequently, when androgen or estrogen deprivation occurs there is aresultant increase in the rate of bone remodeling that tilts the balanceof resorption and formation to the favor of resorption that contributesto the overall loss of bone mass. In males, the natural decline insex-hormones at maturity (direct decline in androgens as well as lowerlevels of estrogens derived from peripheral aromatization of androgens)is associated with the frailty of bones. This effect is also observed inmales who have been castrated.

Muscle wasting refers to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles, which control movement, cardiac muscles,which control the heart (cardiomyopathics), and smooth muscles. Chronicmuscle wasting is a chronic condition (i.e. persisting over a longperiod of time) characterized by progressive loss of muscle mass,weakening and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by muscle protein degradation by catabolism. Proteincatabolism occurs because of an unusually high rate of proteindegradation, an unusually low rate of protein synthesis, or acombination of both. Muscle protein catabolism, whether caused by a highdegree of protein degradation or a low degree of protein synthesis,leads to a decrease in muscle mass and to muscle wasting.

Muscle wasting is associated with chronic, neurological, genetic orinfectious pathologies, diseases, illnesses or conditions. These includemuscular dystrophies such as Duchenne muscular dystrophy and myotonicdystrophy; muscle atrophies such as post-polio muscle atrophy (PPMA);cachexias such as cardiac cachexia, aids cachexia and cancer cachexia,malnutrition, leprosy, diabetes, renal disease, chronic obstructivepulmonary disease (COPD), cancer, end stage renal failure, sarcopenia,emphysema, osteomalacia, HIV infection, AIDS, and cardiomyopathy.

In addition, other circumstances and conditions are linked to and cancause muscle wasting. These include chronic lower back pain, advancedage, central nervous system (CNS) injury, peripheral nerve injury,spinal cord injury, chemical injury, central nervous system (CNS)damage, peripheral nerve damage, spinal cord damage, chemical damage,burns, disuse deconditioning that occurs when a limb is immobilized,long term hospitalization due to illness or injury, and alcoholism.

An intact androgen receptor (AR) signaling pathway is crucial forappropriate development of skeletal muscles. Furthermore, an intactAR-signaling pathway increases lean muscle mass, muscle strength andmuscle protein synthesis.

Muscle wasting, if left unabated, can have dire health consequences. Forexample, the changes that occur during muscle wasting can lead to aweakened physical state that is detrimental to an individual's health,resulting in increased susceptibility to bone fracture and poor physicalperformance status. In addition, muscle wasting is a strong predictor ofmorbidity and mortality in patients suffering from cachexia and AIDS.

New innovative approaches are urgently needed at both the basic scienceand clinical levels to develop compounds which are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with Androgen Decline in Aging Male(ADAM), such as fatigue, depression, decreased libido, sexualdysfunction, erectile dysfunction, hypogonadism, osteoporosis, hairloss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benignprostate hyperplasia, alterations in mood and cognition and prostatecancer; c) treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of chronic muscularwasting or sarcopenia; e) decreasing the incidence of, halting orcausing a regression of prostate cancer; f) oral androgen replacementand/or other clinical therapeutic and/or diagnostic areas.

A wide variety of diseases and/or conditions are affected byhypogonadism, and catabolic effects, including kidney disease, centralnervous system injuries, burns and chronic wounds.

In the United States (US), there is a rising incidence and prevalence ofkidney failure. The number of patients enrolled in end-stage renaldisease (ESRD) Medicare-funded programs has increased from approximately10,000 beneficiaries in 1973 to 86,354 in 1983, and to 431,284 as ofDec. 31, 2002. In 2002 alone, 100,359 patients entered the US ESRDprogram. Chronic kidney disease (CKD) is a precursor to ESRD and occurswhen the kidneys are not able to adequately remove wastes from the body.CKD is a slowly progressing disease, in which diabetes, hypertension andanemia may be co-morbid conditions.

CKD is diagnosed using a staging system that demonstrates the amount ofkidney function available (stage 1=normal kidney function) and patientsoften do not present symptoms in the early stages. Stage 5 of CKD isESRD, which is a complete or near complete failure of the kidneys andusually occurs when kidney function is less than 10% of baseline.

Accompanying symptoms associated with ESRD include hypogonadism,involuntary weight loss, fatigue and others.

Burns result in a testosterone reduction, nitrogen level reduction and areduction in bone mineral density (BMD), which may persist even as longone year following the injury and is associated with impaired woundhealing, increased infection risks, erosion of lean body mass, hamperedrehabilitation, and delayed reintegration of burn survivors intosociety. Catabolic effects initiated as a result of the burn lead tosignificant involuntary weight loss, further compounding the problem.

Spinal cord injuries (SCI) may result in the alteration centralneurotransmitter secretion or production, which in turn may cause ahypothalamus-pituitary-adrenal axis dysfunction, leading to decreases intestosterone and other hormone levels. SCI or other acute illness ortrauma characteristically includes heightened catabolism in conjunctionwith the lowered anabolic activity resulting in a condition that isprone to loss of lean body tissue. As long as the catabolic process goesuninterrupted, disturbed nutrient utilization will continue. The effectsof the loss of lean body mass include the development of wounds andimpaired healing mechanisms. Because of poor nutrition and proteincombined with immobilization, patients with spinal cord injury are athigh risk for bed sores.

Chronic wounds may be caused by any number of conditions, includingdiabetes, circulatory problems, immobilization and others. Compoundingthe problem, for example in diabetes, is the presence of neuropathy,which increases the risk of foot ulceration.

While there are many treatments and therapies for these conditions, noneare ideal. Since the androgen receptor (AR) signaling pathway has beenshown to increase lean muscle mass, muscle strength and muscle proteinsynthesis, and since hypogonadism accompanies these conditions,molecules targeting the AR signaling pathway may be useful in treatingthese diseases and/or conditions.

SUMMARY OF THE INVENTION

In one embodiment, this invention provides a compound represented by thestructure of formula I:

-   -   wherein    -   X is C or N; W is C or N;    -   X₁ is N, NH, N(C₁₋₄alkyl), NAc, NCOOH or a bond; or X₁ and X₃        together with X₂ and X₅ to which X₁ and X₃ are attached, form a        saturated or unsaturated, substituted or unsubstituted 5- or        6-membered ring; or X₁ and X₅ together with X₂ to which X₁ and        X₅ are attached form a saturated or unsaturated, substituted or        unsubstituted 5- or 6-membered ring and A is nothing;    -   P is H or formula II:

-   -   -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond; or X₂            and R₃ together with X₁, to which X₂ is attached, form a            ring, which is a saturated or unsaturated, substituted or            unsubstituted 5 or 6 membered ring; or X₂ and X₅ form a            saturated or unsaturated, substituted or unsubstituted 5- or            6-membered ring and A is nothing;        -   X₃ is C₁₋₄ alkylene, NH, N, CH(OH), a bond, or X₃ and X₁            together with X₂ and X₅ to which X₁ and X₃ are attached form            a saturated or unsaturated, substituted or unsubstituted 5-            or 6-membered ring; or X₃ and X₅ form a saturated or            unsaturated, substituted or unsubstituted 5- or 6-membered            ring and A is nothing; or X₃ and X₄ form together a double            bond or form together a saturated or unsaturated,            substituted or unsubstituted 3 to 6 membered ring.        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond; or X₄ and X₅ together with X₃, to which X₄ and X₅ are            attached form a saturated or unsaturated membered,            substituted or unsubstituted 5- or 6-membered ring and A is            nothing; or X₃ and X₄ form together a double bond or form a            saturated or unsaturated, substituted or unsubstituted 3 to            6 membered ring.        -   X₅ is a carbon or X₅ and X₁ together with X₂ to which X₁ and            X₅ are attached form a saturated or unsaturated, substituted            or unsubstituted 5- or 6-membered ring and A is nothing; or            X₅ and X₂ form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing; or X₅            and X₃ form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing; or X₅            and X₄ together with X₃, to which X₅ and X₄ are attached            form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing.        -   A is nothing, H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃,            CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,            CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,            C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂CF₃, CF₂CF₃,            CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂; or A with R forms a            double bond represented by formula III:

-   -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, halide, CF₃, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, NH₂, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN, NO₂; or R₃ and X₂ together with        the benzene ring to which R₃ is attached and X₁ to which X₂ is        attached form a ring, which is a saturated or unsaturated,        substituted or unsubstituted 5- or 6-membered ring;        -   R′ is NH₂, OH or CH₃;    -   R₄ and R₅ are independently H, CH₃, halide, OH, C₁₋₄alkyl,        C₁₋₆cycloalkyl, halo(C₁₋₄alkyl), phenyl, aryl,        C₄₋₈heterocycloalkyl, or hydroxy(C₁₋₄alkyl);    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide;    -   wherein    -   if P is formula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R        is OH and A is alkyl or haloalkyl, then X₄ is        S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        N[CH₂CH₂N(CH₃)₂], P(O)(C₁₋₄alkyl) or N(O)[CH₂CH₂N(CH₃)₂];    -   or    -   if P is formula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R        is OH or OAlk and X₄ is O, S, NH, S, SO, SO₂ or alkylene, then A        is CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,        CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄        alkyl), C(O)R′, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   or    -   if P is phenyl, X is C, X₁ is NH, X₂ is C(O), R is OH and A is        COOH, X₃ is a bond, X₄ is CH₂, R₁, R₂ are H then Q is not H.    -   or    -   if P is formula II, X is C, X₃ is CH₂, X₄ is O, or NH, R₁, R₂        and R₃ are H, and X₅ and X forms a 5 membered ring, an        oxazolidine-2-one then Q is not halogen, or H;    -   or    -   if P is H, X is C, X₁ is NH, X₂ is C(O), R is OH, A is alkyl, X₃        is a bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H, then Q        is not H or halogen.

In another embodiment, compound of formula I, is represented by thefollowing structure:

In another embodiment, compound of formula I, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula IV:

-   -   wherein        -   X is C or N; W is C or N;        -   X₂ is C₁₋₄alkylene, SO₂, CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or            O(C₁₋₄acyl);        -   R₁ is H, OH, NH₂, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula IV, is represented by thefollowing structure:

In another embodiment, compound of formula IV, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula VI:

-   -   wherein        -   X is C or N; W is C or N        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or            O(C₁₋₄acyl);        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula VI, is represented by thefollowing structure:

In one embodiment, the compound of formula VI, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XII:

-   -   wherein        -   X is C or N; W is C or N;        -   X₄ is O, S, SO, S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,            C₁₋₄alkylene, C(OH) [CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN,            CH₂N₃, CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,            C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂OR′CH₂C(O)CH═CH₂ or            C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula XII, is represented by thefollowing structure:

In another embodiment, compound of formula XII, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XIII:

-   -   wherein A is as described above, in compound XII.

In one embodiment, this invention provides a compound represented by thestructure of formula XIII:

In one embodiment, this invention provides a compound represented by thestructure of formula XVII:

-   -   wherein    -   X₄ is S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂],        C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂],        NO[CH₂CH₂N(CH₃)₂];    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; and    -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br.

In another embodiment, compound of formula XVII, is represented by thefollowing structure:

In another embodiment, compound of formula XVII, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XIX:

-   -   wherein        -   X is C or N; W is C or N        -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;        -   X₃ is C₁₋₄ alkylene, NH, N, CH(OH) or a bond;        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide;        -   wherein        -   if X is C, X₁ is NH, X₂ is C(O), R is OH, A is alkyl, X₃ is            a bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H, then Q            is not H or halogen.

In another embodiment, compound of formula XIX, is represented by thefollowing structure:

In another embodiment, compound of formula XIX, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XX:

-   -   wherein        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F; Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula I, is represented by thefollowing structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of compound XXI:

-   -   wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in compound        XX.

In another embodiment, compound of formula XXI, is represented by thefollowing structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of compound XXII:

-   -   wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in compound        XX, R₇ is H or oxo and R₈ is H or ═CH₂.

In another embodiment, compound of formula XXII, is represented by thefollowing structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of formula XXIII:

-   -   wherein    -   X is C or N; W is C or N        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIII:

wherein Z, Y, X₄, Q, R₁, R₂ and R₃ are as described in compound XXIII.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIV:

-   -   wherein        -   X is C or N; W is C or N        -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH) [CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXVII:

-   -   wherein    -   X, X₂, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above in        compound XXXIV.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXVIII:

-   -   wherein X, X₂, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above        in compound XXXIV.

In another embodiment, compound of formula XXXVIII, is represented bythe following structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIX:

-   -   wherein:    -   X is C or N; W is C or N;    -   G is O, NH, NC₁₋₄alkyl, NC₁₋₄acyl, S, CHC₁₋₄alkyl, CHC₁₋₄acyl,        C(C₁₋₄acyl)₂, C(C₁₋₄alkyl)₂ or (CH₂)_(n), where n is 1-3;    -   T is S or O;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound of formula XLII:

-   -   wherein X, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above in        compound XXXIX.

In one embodiment, this invention provides a compound of formula XLIV:

-   -   wherein:    -   X, X₄, R, R₁, R₂, R₃, Z, Y and Q are as described above in        compound XXXIX;    -   wherein    -   if X is C, X₄ is O, NH, or S, R₁, R₂ and R₃ are H and R is H        then Q is not halogen, H or CN.

In another embodiment, compound of formula XLIV, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XLVII:

In one embodiment, the present invention provides a compositioncomprising a compound of formula (I) and/or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof.

In one embodiment, the compound is a selective androgen receptormodulator (SARM). In one embodiment, the SARM is a partial agonist. Inone embodiment, the SARM is a tissue-selective agonist, or in someembodiments, a tissue-selective antagonist.

In one embodiment, this invention provides a method of contraception ina male subject, comprising the step of administering to the subject acompound of formula (I) and/or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof, or a composition comprising the same, in an amounteffective to suppress sperm production in the subject, thereby effectingcontraception in the subject.

In one embodiment, this invention provides a method of hormone therapycomprising the step of contacting an androgen receptor of a subject witha compound of formula (I) and/or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof, or a composition comprising the same, in an amounteffective to effect a change in an androgen-dependent condition.

In one embodiment, this invention provides a method of treating asubject suffering from prostate cancer, comprising the step ofadministering to said subject a compound of formula (I), and/or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof, or a compositioncomprising the same in an amount effective to treat prostate cancer inthe subject.

In one embodiment, this invention provides a method of delaying theprogression of prostate cancer in a subject suffering from prostatecancer, comprising the step of administering to said subject a compoundof formula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, or a composition comprising the same in an amount effective todelay the progression of prostate cancer in the subject.

In one embodiment, this invention provides a method of treating abone-related disorder in a subject, or increasing a bone mass in asubject, promoting bone formation in a subject, administering aneffective amount of a compound of formula (I) and/or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof, or a composition comprisingthe same, in an amount effective to treat said bone-related disorder.

According to this aspect, and in one embodiment, the subject suffersfrom osteoporosis, osteopenia, increased bone resorption, bone fracture,bone frailty, loss of bone mineral density (BMD), or any combinationthereof. In one embodiment, the method increases the strength of a boneof said subject. In one embodiment, the compound stimulates or enhancesosteoblastogenesis, or in another embodiment the compound inhibitsosteoclast proliferation.

In one embodiment, this invention provides a method of treating,reducing the incidence of, delaying progression of, reducing theseverity of, or alleviating symptoms associated with a muscle wastingdisorder in a subject, comprising the step of administering to saidsubject a compound of formula (I) and/or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof, or a composition comprising the same, in anamount effective to treat the muscle wasting disorder in said subject.

According to this aspect, and in one embodiment, the muscle wastingdisorder is due to a pathology, illness, disease or condition. In oneembodiment, the pathology, illness, disease or condition isneurological, infectious, chronic or genetic. In one embodiment, thepathology, illness, disease or condition is a muscular dystrophy, amuscular atrophy, X-linked spinal-bulbar muscular atrophy (SBMA), aCachexia, malnutrition, leprosy, diabetes, renal disease, chronicobstructive pulmonary disease (COPD), cancer, end stage renal failure,sarcopenia, emphysema, osteomalacia, HIV infection, AIDS, orcardiomyopathy.

In one embodiment, the muscle wasting disorder is an age-associatedmuscle wasting disorder; a disuse deconditioning-associated musclewasting disorder; or the muscle wasting disorder is due to chronic lowerback pain; burns; central nervous system (CNS) injury or damage;peripheral nerve injury or damage; spinal cord injury or damage;chemical injury or damage; or alcoholism.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of diabetes in a human subject, comprisingadministering an effective amount of a compound of formula (I) and/orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof, to said subject.

In one embodiment, this invention provides, a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of glucose intolerance in a human subject,comprising the step of administering an effective amount of a compoundof formula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of hyperinsulinemia in a human subject,comprising the step of administering an effective amount of a compoundof formula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of insulin resistance in a human subject,comprising the step of administering an effective amount of a compoundof formula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of diseases associated with diabetescomprising the step of administering an effective amount of a compoundof formula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of fatty liver conditions in a humansubject, comprising the step of administering an effective amount of acompound of formula (I) and/or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof, to said subject.

In one embodiment, this invention provides a method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing the pathogenesis of cardiovascular disease in a humansubject, comprising the step of administering an effective amount of acompound of formula (I) and/or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof to said subject.

In one embodiment, this invention provides a method of treating reducingthe severity of, reducing the incidence of, delaying the onset of, orreducing the pathogenesis of cachexia in a subject, comprising the stepof administering an effective amount of a compound of formula (I) and/orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof to said subject.

In one embodiment, this invention provides a method of treating adisease or condition of the eye of a subject, comprising the step ofadministering an effective amount of a compound of formula (I) and/orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof, to the subject. Inone embodiment, the disease or condition of the eye comprises Sjogren'ssyndrome, or xerophthalmia.

In one embodiment, the present invention provides a method of reducing afat mass in a subject comprising the step of administering an effectiveamount of a compound of formula (I) and/or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof, to the subject.

In one embodiment, the present invention provides a method of increasinga lean mass in a subject comprising the step of administering aneffective amount of a compound of formula (I) and/or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof, to the subject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of cachexia in a subject, comprising thestep of administering to said subject a compound of formula (I) and/orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof, to the subject.

In one embodiment, the cachexia is associated with cancer in saidsubject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of rheumatoid arthritis in a subject,comprising the step of administering to said subject a compound offormula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to the subject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of chronic kidney disease in a subject,comprising the step of administering to said subject a compound offormula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to the subject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of end stage renal disease in a subject,comprising the step of administering to said subject a compound offormula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to the subject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of frailty in a subject, comprising thestep of administering to said subject a compound of formula (I) and/orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof, to the subject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of hypogonadism in a subject, comprisingthe step of administering to said subject a compound of formula (I)and/or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, N-oxide, hydrate or any combination thereof, to thesubject.

In another embodiment, this invention provides a method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of age-related functional decline in asubject, comprising the step of administering to said subject a compoundof formula (I) and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, to the subject.

In another embodiment, this invention provides a method of suppressingspermatogenesis; contraception in a male; hormone therapy; treatingprostate cancer; delaying the progression of prostate cancer; treating abone-related disorder in a subject, or increasing a bone mass in asubject and/or promoting bone formation in a subject; treating, reducingthe incidence of, delaying progression of, reducing the severity of, oralleviating symptoms associated with a muscle wasting disorder;treating, reducing the severity of, reducing the incidence of, delayingthe onset of, or reducing pathogenesis of diabetes; treating, reducingthe severity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of glucose intolerance; treating, reducing theseverity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of hyperinsulinemia; treating, reducing theseverity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of insulin resistance; treating, reducing theseverity of, reducing the incidence of, delaying the onset of, orreducing pathogenesis of diseases associated with diabetes; treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of fatty liver conditions; treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of cardiovascular disease; treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of cachexia; treating a disease orcondition of the eye; reducing a fat mass; or increasing a lean mass ina subject, comprising the step of administering an effective amount of acompound of formula (I) and/or its isomer, pharmaceutically acceptablesalt, pharmaceutical product, crystal, N-oxide, hydrate or anycombination thereof, to the subject as herein described.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter regarded as the invention is particularly pointed outand distinctly claimed in the concluding portion of the specification.The invention, however, both as to organization and method of operation,together with objects, features, and advantages thereof, may best beunderstood by reference to the following detailed description when readwith the accompanying drawings in which:

FIG. 1 depicts various selective androgen receptor modulator analogstructures (FIG. 1A) and their synthetic schemes such as for compoundXIII (FIG. 1B); compound V (FIG. 1C); compounds of formula XI (FIG. 1D);compound XXXV (FIG. 1E); compound XXXVI (FIG. 1F), compound XLVI (FIG.1G); compound X (FIG. 1H); Compounds XXIV-XXVIII (FIG. 1I).Compound XL(FIG. 1J); Compound XLI (FIG. 1K)

FIG. 2 depicts synthetic scheme for preparing compound of formula XLIII(oxatidyldione).

FIG. 3 depicts synthetic scheme for preparing compound of formulaXLVIII.

FIG. 4 depicts synthetic scheme for preparing compound of formula XLIX.

FIG. 5 depicts synthetic scheme for preparing compound of formula LII.

FIG. 6 depicts synthetic scheme for preparing compound of formula L.

FIG. 7 depicts synthetic scheme for preparing compound of formula LI.

FIG. 8 depicts transcriptional activation of bicalutamide analogs viathe wild type androgen receptor. CV-1 cells were transiently transfectedwith hAR and androgen-dependent luciferase reporter construct, prior totreatment with the indicated ligand. Fold increase relative tovehicle-treated controls is reported (n=6).

FIG. 9 depicts the androgenic and anabolic activity of S-4 shown inTable 1 (FIG. 9A) and of testosterone (FIG. 9B) in castrated rats.Castrated male rats received increasing doses of testosterone (toppanel) or S-4 (bottom) for 14 days. Organ weights as a percentage ofintact control were determined at sacrifice.

FIG. 10 depicts superimposed carbon-bound hydrogen suppressedball-and-stick models colored by atom with S-4, S-1, X-2, X-3, X-5 andX-4 (X═O, O, S, SO₂, CH₂, and NH, respectively) as shown in Table 1. Theagonists S-4 and X-2 as well as S-1 demonstrated a six-membered annularNH to X hydrogen bonding configuration not previously postulated foraryl propionamides.

FIG. 11 depicts the transcriptional activation via WT or mutant androgenreceptor for DHT, hydroxyflutamide (HF), bicalutamide (bical) and S-4.CV-1 cells were transiently transfected with expression vectors for WTor mutant AR and an androgen-dependent reporter gene construct.AR-mediated induced by each drug (100 nM) is reported as a relativeluciferase units divided by β-galactosidase activity (normalizationcontrol).

FIG. 12 depicts the crystal structures of the androgen receptorligand-binding domain (AR LBD). FIG. 12A presents the front view of theglobal architecture of mutant AR LBD (W741L) bound with R-bicalutamide.FIG. 12B presents electron density maps of W741L-R-bicalutamide andR-bicalutamide within the Fo-Fc simulates annealing omit map withR-bicalutamide omitted.

FIG. 13 depicts an overlay of WT-DHT, T877A-HF, and W741L-R-bicalutamidein stereo, showing an overview of the steroidal binding plane (FIG. 13A)and the side view of the steroidal binding plane (FIG. 13B).

FIG. 14 depicts the mutant W741L androgen receptor ligand binding domainbound with R-bicalutamide. FIG. 14A presents the side view globalarchitecture of AR LBD (W741L) bound with R-bicalutamide. The AF2 region(helices 3, 4, and 12) are highlighted in green. The conservedcharge-clamp residues are K720 in H3 and E897 in H12. FIG. 14B presentsthe structural details of the AF2 region in wild type AR LBD bound withDHT. W741 side chain is shown in space filled atoms.

It will be appreciated that for simplicity and clarity of illustration,elements shown in the figures have not necessarily been drawn to scale.For example, the dimensions of some of the elements may be exaggeratedrelative to other elements for clarity. Further, where consideredappropriate, reference numerals may be repeated among the figures toindicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the following detailed description, numerous specific details are setforth in order to provide a thorough understanding of the invention.However, it will be understood by those skilled in the art that thepresent invention may be practiced without these specific details. Inother instances, well-known methods, procedures, and components have notbeen described in detail so as not to obscure the present invention.

In one embodiment, this invention provides a compound represented by thestructure of formula I:

-   -   wherein    -   X is C or N; W is C or N;    -   X₁ is N, NH, N(C₁₋₄alkyl), NAc, NCOOH or a bond; or X₁ and X₃        together with X₂ and X₅ to which X₁ and X₃ are attached, form a        saturated or unsaturated, substituted or unsubstituted 5- or        6-membered ring; or X₁ and X₅ together with X₂ to which X₁ and        X₅ are attached form a saturated or unsaturated, substituted or        unsubstituted 5- or 6-membered ring and A is nothing;    -   P is H or formula II:

-   -   -   X₂ is C₁₋₄alkylne, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond; or X₂            and R₃ together with X₁, to which X₂ is attached, form a            ring, which is a saturated or unsaturated, substituted or            unsubstituted 5 or 6 membered ring; or X₂ and X₅ form a            saturated or unsaturated, substituted or unsubstituted 5- or            6-membered ring and A is nothing;        -   X₃ is C₁₋₄ alkylene, NH, N, CH(OH), a bond, or X₃ and X₁            together with X₂ and X₅ to which X₁ and X₃ are attached form            a saturated or unsaturated, substituted or unsubstituted 5-            or 6-membered ring; or X₃ and X₅ form a saturated or            unsaturated, substituted or unsubstituted 5- or 6-membered            ring and A is nothing; or X₃ and X₄ form together a double            bond or form together a saturated or unsaturated,            substituted or unsubstituted 3 to 6 membered ring.        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond; or X₄ and X₅ together with X₃, to which X₄ and X₅ are            attached form a saturated or unsaturated membered,            substituted or unsubstituted 5- or 6-membered ring and A is            nothing; or X₃ and X₄ form together a double bond or form            together a saturated or unsaturated, substituted or            unsubstituted 3 to 6 membered ring.        -   X₅ is a carbon or X₅ and X₁ together with X₂ to which X₁ and            X₅ are attached form a saturated or unsaturated, substituted            or unsubstituted 5- or 6-membered ring and A is nothing; or            X₅ and X₂ form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing; or X₅            and X₃ form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing; or X₅            and X₄ together with X₃, to which X₅ and X₄ are attached            form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing.        -   A is nothing, H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃,            CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,            CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,            C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂CF₃, CF₂CF₃,            CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂; or A with R forms a            double bond represented by formula III:

-   -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, halide, CF₃, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂;        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, NH₂, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN, NO₂; or R₃ and X₂ together with        the benzene ring to which R₃ is attached and X₁ to which X₂ is        attached form a ring, which is a saturated or unsaturated,        substituted or unsubstituted 5- or 6-membered ring;    -   R′ is NH₂, OH or CH₃;    -   R₄ and R₅ are independently H, CH₃, halide, OH, C₁₋₄alkyl,        C₁₋₆cycloalkyl, halo(C₁₋₄alkyl), phenyl, aryl,        C₄₋₈heterocycloalkyl, or hydroxy(C₁₋₄alkyl);    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide;    -   wherein    -   if P is formula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R        is OH and A is alkyl or haloalkyl, then X₄ is        S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        N[CH₂CH₂N(CH₃)₂], P(O)(C₁₋₄alkyl) or N(O)[CH₂CH₂N(CH₃)₂];    -   or    -   if P is formula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R        is OH or OAlk and X₄ is O, S, NH, S, SO, SO₂ or alkylene, then A        is CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,        CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄        alkyl), C(O)R′, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   or    -   if P is phenyl, X is C, X is NH, X₂ is C(O), R is OH and A is        COOH, X₃ is a bond, X₄ is CH₂, R₁, R₂ are H then Q is not H.    -   or    -   if P is formula II, X is C, X₃ is CH₂, X₄ is O, or NH, R₁, R₂        and R₃ are H, and X₅ and X forms a 5 membered ring, an        oxazolidine-2-one then Q is not halogen, or H;    -   or    -   if P is H, X is C, X is NH, X₂ is C(O); R is OH, A is alkyl, X₃        is a bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H, then Q        is not H or halogen.

In another embodiment, compound of formula I, is represented by thefollowing structure:

In another embodiment, compound of formula I, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula IV:

-   -   wherein        -   X is C or N; W is C or N;        -   X₂ is C₁₋₄alkylene, SO₂, CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN; NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or            O(C₁₋₄acyl);        -   R₁ is H, OH, NH₂, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula IV, is represented by thefollowing structure:

In another embodiment, compound of formula IV, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula VI:

wherein

-   -   X is C or N; W is C or N    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a bond;    -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,        CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,        C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′,        CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₄acyl);    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula VI, is represented by thefollowing structure:

In one embodiment, the compound of formula VI, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XII:

wherein

-   -   X is C or N; W is C or N;    -   X₄ is O, S, SO, S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a bond;    -   A is CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,        CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,        C(O)O(C₁₋₄alkyl), C(O)R′, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula XII, is represented by thefollowing structure:

In another embodiment, compound of formula XI, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XIII:

wherein A is as described above, in compound XII.

In one embodiment, this invention provides a compound represented by thestructure of formula XIII:

In one embodiment, this invention provides a compound represented by thestructure of formula XVII:

wherein

X₄ is S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂];

Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl, C(O)CH₂NH₂,C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂, NH(C₁₋₄alkyl),NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂, NHCO(C₁₋₄alkyl),NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₄₋₈cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(CH₃)₂];

Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; and

Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br.

In another embodiment, compound of formula XVII, is represented by thefollowing structure:

In another embodiment, compound of formula XVII, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XIX:

wherein

-   -   X is C or N; W is C or N    -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄        alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;    -   X₃ is C₁₋₄ alkylene, NH, N, CH(OH) or a bond;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH) [CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,        CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,        C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′,        CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide;    -   wherein    -   if X is C, X₁ is NH, X₂ is C(O), R is OH, A is alkyl, X₃ is a        bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H, then Q is        not H or halogen.

In another embodiment, compound of formula XIX, is represented by thefollowing structure:

In another embodiment, compound of formula XIX, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XX:

wherein

-   -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃; CN, CH₂OH,        CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,        C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′,        CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F; Cl, I or Br;    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, compound of formula I, is represented by thefollowing structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of compound XXI:

-   -   wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in compound        XX.

In another embodiment, compound of formula XXI, is represented by thefollowing structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of compound XXII:

-   -   wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in compound        XX, R₇ is H or oxo and R₈ is H or ═CH₂.

In another embodiment, compound of formula XXII, is represented by thefollowing structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of formula XXIII:

-   -   wherein    -   X is C or N; W is C or N        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIII:

wherein Z, Y, X₄, Q, R₁, R₂ and R₃ are as described in compound XXIII.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIV:

wherein

-   -   X is C or N; W is C or N    -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄        alkyl), CH(NH₂), CH(OH), CH(C₁₋₄haloalkyl), a bond;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXVII:

wherein

X, X₂, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above in compoundXXXIV.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXVIII:

wherein X, X₂, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above incompound XXXIV.

In another embodiment, compound of formula XXXVIII, is represented bythe following structure:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIX:

-   -   wherein:    -   X is C or N; W is C or N;    -   G is O, NH, NC₁₋₄alkyl, NC₁₋₄acyl, S, CHC₁₋₄alkyl, CH₁₋₄acyl,        C(C₄acyl)₂, C(C₁₋₄alkyl)₂ or (CH₂)_(n), where n is 1-3;    -   T is S or O;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound of formula XLII:

wherein X, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above in compoundXXXIX.

In one embodiment, this invention provides a compound of formula XLIV:

-   -   wherein:    -   X, X₄, R, R₁, R₂, R₃, Z, Y and Q are as described above in        compound XXXIX;    -   wherein    -   if X is C, X₄ is O, NH, or S, R₁, R₂ and R₃ are H and R is H        then Q is not halogen, H or CN.

In another embodiment, compound of formula XLIV, is represented by thefollowing structure:

In one embodiment, this invention provides a compound represented by thestructure of formula XLVII:

In one embodiment, this invention provides a compound represented by thestructure of formula I:

-   -   wherein    -   X is C or N; W is C or N;    -   X₁ is N, NH, N(C₁₋₄alkyl), NAc, NCOOH or a bond; or X₁ and X₃        together with X₂ and X₅ to which X₁ and X₃ are attached, form a        saturated or unsaturated, substituted or unsubstituted 5- or        6-membered ring; or X₁ and X₅ together with X₂ to which X₁ and        X₅ are attached form a saturated or unsaturated, substituted or        unsubstituted 5- or 6-membered ring and A is nothing;    -   P is H or formula II:

-   -   -   X₂ is C₁₋₄alkylne, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond; or X₂            and R₃ together with X₁, to which X₂ is attached, form a            ring, which is a saturated or unsaturated, substituted or            unsubstituted 5 or 6 membered ring; or X₂ and X₅ form a            saturated or unsaturated, substituted or unsubstituted 5- or            6-membered ring and A is nothing;        -   X₃ is C₁₋₄ alkylene, NH, N, CH(OH), a bond, or X₃ and X₁            together with X₂ and X₅ to which X₁ and X₃ are attached form            a saturated or unsaturated, substituted or unsubstituted 5-            or 6-membered ring; or X₃ and X₅ form a saturated or            unsaturated, substituted or unsubstituted 5- or 6-membered            ring and A is nothing; or X₃ and X₄ form together a double            bond or form together a saturated or unsaturated,            substituted or unsubstituted 3 to 6 membered ring.        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond; or X₄ and X₅ together with X₃, to which X₄ and X₅ are            attached form a saturated or unsaturated membered,            substituted or unsubstituted 5- or 6-membered ring and A is            nothing; or X₃ and X₄ form together a double bond or form a            saturated or unsaturated, substituted or unsubstituted 3 to            6 membered ring.        -   X₅ is a carbon or X₅ and X₁ together with X₂ to which X₁ and            X₅ are attached form a saturated or unsaturated, substituted            or unsubstituted 5- or 6-membered ring and A is nothing; or            X₅ and X₂ form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing; or X₅            and X₃ form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing; or X₅            and X₄ together with X₃, to which X₅ and X₄ are attached            form a saturated or unsaturated, substituted or            unsubstituted 5- or 6-membered ring and A is nothing.        -   A is nothing, H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃,            CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,            CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,            C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂CF₃, CF₂CF₃,            CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂; or A with R forms a            double bond represented by formula III:

-   -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂,CN, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, halide, CF₃, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN, NO₂; or R₃ and X₂ together with        the benzene ring to which R₃ is attached and X₁ to which X₂ is        attached form a ring, which is a saturated or unsaturated,        substituted or unsubstituted 5- or 6-membered ring;        -   R′ is NH₂, OH or CH₃;    -   R₄ and R₅ are independently H, CH₃, halide, OH, C₁₋₄alkyl,        C₁₋₆cycloalkyl, halo(C₁₋₄alkyl), phenyl, aryl,        C₄₋₈heterocycloalkyl, or hydroxy(C₁₋₄alkyl);    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide;    -   wherein    -   if P is formula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R        is OH and A is alkyl or haloalkyl, then X₄ is        S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        N[CH₂CH₂N(CH₃)₂], P(O)(C₁₋₄alkyl) or N(O)[CH₂CH₂N(CH₃)₂];    -   or    -   if P is formula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R        is OH or OAlk and X₄ is O, S, NH, S, SO, SO₂ or alkylene, then A        is CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃,        CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄        alkyl), C(O)R′, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;    -   or    -   if P is phenyl, X is C, X₁ is NH, X₂ is C(O), R is OH and A is        COOH, X₃ is a bond, X₄ is CH₂, R₁, R₂ are H then Q is not H.    -   or    -   if P is formula II, X is C, X₃ is CH₂, X₄ is O, or NH, R₁, R₂        and R₃ are H, and X₅ and X₁ forms a 5 membered ring, an        oxazolidine-2-one then Q is not halogen, or H;    -   or    -   if P is H, X is C, X₁ is NH, X₂ is C(O), R is OH, A is alkyl, X₃        is a bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H, then Q        is not H or halogen;    -   or    -   if P is formula II, R₃ is H, X and W are C, X₁ and X₅ together        with X₂ to which X₁ and X₅ are attached form a oxazolidinedione,        R is alkyl, X₃ is CH₂ and X₄ is O, NH, S, SO₂, or CH₂, then Q is        not an halide.

In one embodiment, this invention provides a compound represented by thestructure of formula IV:

-   -   wherein        -   X is C or N; W is C or N;        -   X₂ is C₁₋₄alkylene, SO₂, CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or            O(C₁₋₄acyl);        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula V:

In one embodiment, this invention provides a compound represented by thestructure of formula VI:

-   -   wherein        -   X is C or N; W is C or N        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH) [CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or            O(C₁₋₄acyl);        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula VII:

wherein Z, Y, R₁, R₂, R₃, Q and X₄ are as described above in compoundVI.

In another embodiment, this invention provides a compound represented bythe structure of formula VIII:

-   -   wherein R₁, R₂, Q and X₄ are as described above, in compound VI.

In one embodiment, this invention provides a compound represented by thestructure of formula IX:

In one embodiment, this invention provides a compound represented by thestructure of formula X:

In one embodiment, this invention provides a compound represented by thestructure of formula XI:

-   -   wherein A is as described above, in compound VI.

In another embodiment, A of compound XI is CH₂OH. In another embodiment,A of compound XI is CH₂OMe. In another embodiment, A of compound XI isCF₃. In another embodiment, A of compound XI is CH₃. In anotherembodiment, A of compound XI is CN.

In one embodiment, this invention provides a compound represented by thestructure of formula XII:

-   -   wherein        -   X is C or N; W is C or N;        -   X₄ is O, S, SO, S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,            C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a            bond;        -   A is CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN,            CH₂N₃, CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,            C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂OR′ CH₂C(O)CH═CH₂ or            C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, X₄ of compound XII is O. In another embodiment, Qof compound XII is CN and R₁ and R₂ are H. In another embodiment, Q ofcompound XII is CN, Z is CN, Y is CF₃ and R₁, R₂ and R₃ are H. Inanother embodiment, A of compound XII is CH₂OH. In another embodiment, Aof compound XII is CN.

In one embodiment, this invention provides a compound represented by thestructure of formula XIII:

-   -   wherein A is as described above, in compound XII.

In one embodiment, this invention provides a compound represented by thestructure of formula XIV:

-   -   or in another embodiment,

In one embodiment, this invention provides a compound represented by thestructure of formula XV:

In one embodiment, this invention provides a compound represented by thestructure of formula XVI:

In one embodiment, this invention provides a compound represented by thestructure of formula XVII:

-   -   wherein    -   X₄ is S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂],        C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂],        NO[CH₂CH₂N(CH₃)₂];    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; and    -   Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br.

In another embodiment, Q of compound XVII is F. In another embodiment, Qof compound XVII is CN. In another embodiment, Z of compound XVII is CNand Y is CF₃. In another embodiment, Q of compound XVII is CN, Z is CNand Y is CF₃.

In one embodiment, this invention provides a compound represented by thestructure of formula XVIII:

In one embodiment, this invention provides a compound represented by thestructure of formula XIX:

In one embodiment, this invention provides a compound of formula I,wherein or X₃ and X₄ form together a double bond or form together asaturated or unsaturated, substituted or unsubstituted 3 to 6 memberedring. In another embodiment, said 3 to 6 membered ring is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, benzene, piperidine, pyrrol, tetrahydrofuran, pyrrolidine,succinimide, oxazolidine, oxazolidinedione or oxazolidinone

In another embodiment, this invention provides a compound represented bythe structure of formula LIII:

In another embodiment, this invention provides a compound represented bythe structure of formula LIV:

-   -   wherein        -   X is C or N; W is C or N        -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄            alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;        -   X₃ is C₁₋₄ alkylene, NH, N, CH(OH) or a bond;        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C [═CHCH₂N(CH₃)₂],            PO(C₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide;        -   wherein        -   if X is C, X₁ is NH, X₂ is C(O), R is OH, A is alkyl, X₃ is            a bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H, then Q            is not H or halogen.

In another embodiment, X₂ of compound XIX is CH₂. In another embodiment,X₂ of compound XIX is C(O). In another embodiment, X₃ of compound XIX isCH₂. In another embodiment, X₄ of compound XIX is O.

In one embodiment, this invention provides a compound of formula I,wherein P is formula II, X₂ and R₃ together with X₁, form a ring, whichis a saturated or unsaturated, substituted or unsubstituted 5- or6-membered ring. In another embodiment said saturated or unsaturated,substituted or unsubstituted 5- or 6-membered ring is pyrrolidine,pyrrole, morpholine, piperidine-4-one, or piperidine.

In one embodiment, this invention provides a compound represented by thestructure of formula XX:

-   -   wherein        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH,            CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,            C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl),            C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, A of compound XX is CH₃. In another embodiment,X₄ of compound XX is O. In another embodiment, Q of compound XX is CN.In another embodiment, Z of compound XX is CN and Y is CF₃. In anotherembodiment, Q of compound XX is CN, Z is CN and Y is CF₃. In anotherembodiment, A of compound XX is CH₃, X₄ is O, Q is CN, Z is CN, R₁ andR₂ are H and Y is CF₃.

In one embodiment, this invention provides a compound represented by thestructure of compound XXI:

-   -   wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in compound        XXI.

In another embodiment, A of compound XXI is CH₃. In another embodiment,X₄ of compound XXI is O. In another embodiment, Q of compound XXI is CN.In another embodiment, Z of compound XXI is CN and Y is CF₃. In anotherembodiment, Q of compound XXI is CN, Z is CN and Y is CF₃. In anotherembodiment, A of compound XXI is CH₃, X₄ is O, Q is CN, Z is CN, R₁ andR₂ are H and Y is CF₃.

In one embodiment, this invention provides a compound represented by thestructure of compound XXII:

-   -   wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in compound        XX, R₇ is H or oxo and R₈ is H or ═CH₂.

In another embodiment, A of compound XXII is CH₃. In another embodiment,X₄ of compound XXII is O. In another embodiment, R₇ and R₈ of compoundXXII are H. In another embodiment R₇ of compound XXII is ═CH₂ and R₈ isoxo. In another embodiment, Q of compound XXII is CN. In anotherembodiment, Z of compound XXII is CN and Y is CF₃. In anotherembodiment, A of compound XXII is CH₃, X₄ is O, Z is CN, Q is CN, R andR₂ are H, and Y is CF₃.

In one embodiment, this invention provides a compound of formula I,wherein P is formula II, X₃ and X₁ together with X₂ and X₅ to which X₁and X₃ are attached form a saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring. In another embodiment saidsaturated or unsaturated, substituted or unsubstituted 5- or 6-memberedring is piperazine, piperazine-2,6-dione, piperidine, pyrrolidine,cyclohexanone, cyclohexane, cyclohexene, cyclopentanone, cyclopentane,cyclopentene, succinimide, oxazolidine, oxazolidinedione oroxazolidinone.

In one embodiment, this invention provides a compound represented by thestructure of formula XXIII:

-   -   wherein    -   X is C or N; W is C or N        -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′,            NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],            PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;        -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;        -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;        -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,            C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,            NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,            NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],            O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)]            or O—[CH₂CH₂N(CH₃)₂];        -   R₁ is H, OH, F, Cl, Br or I;        -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,            CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;        -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;        -   R′ is NH₂, OH or CH₃; and        -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, X₄ of compound XXIII is O. In another embodiment,Q of compound XXIII is CN. In another embodiment, Z of compound XXI isCN and Y is CF₃. In another embodiment, X₄ of compound XXIII is O, Z isCN, Q is CN, R₁, R₂ and R₃ are H, and Y is CF₃.

In another embodiment, this invention provides a compound represented bythe structure of formula XXIV:

In another embodiment, this invention provides a compound represented bythe structure of formula XXV:

In another embodiment, this invention provides a compound represented bythe structure of formula XXVI:

In another embodiment, this invention provides a compound represented bythe structure of formula XXVII:

In another embodiment, this invention provides a compound represented bythe structure of formula XXVIII:

In another embodiment, this invention provides a compound represented bythe structure of formula XXIX:

In another embodiment, this invention provides a compound represented bythe structure of formula XXX:

In another embodiment, this invention provides a compound represented bythe structure of formula XXXI:

In another embodiment, this invention provides a compound represented bythe structure of formula XXXII:

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIII:

wherein Z, Y, X₄, Q, R₁, R₂ and R₃ are as described in compound XXIII.

In another embodiment, X₄ of compound XXXIII is O. In anotherembodiment, Q of compound XXXIII is CN. In another embodiment, Z ofcompound XXXIII is CN and Y is CF₃. In another embodiment, X₄ ofcompound XXXIII is O, Z is CN, Q is CN, R₁, R₂ and R₃ are H, and Y isCF₃.

In one embodiment, this invention provides a compound of formula I,wherein P is formula II, X₃ and X₅ form a saturated or unsaturated,substituted or unsubstituted 5- or 6-membered ring. In anotherembodiment said saturated or unsaturated, substituted or unsubstituted5- or 6-membered ring is tetrahydrofuran, pyrrolidine, piperidine,cyclohexanone, cyclohexane, cyclohexene, cyclohexenone, cyclopentanone,cyclopentenone, cyclopentane, cyclopentene, succinimide, oxazolidine,oxazolidinedione or oxazolidinone.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIV:

wherein

-   -   X is C or N; W is C or N    -   X₂ is C₁₋₄alkylene, SO₂, C(O), CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄        alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl), a bond;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In another embodiment, X₄ of compound XXXIV is O. In another embodiment,Q of compound XXXIV is CN. In another embodiment, X₂ of compound XXXIVis CH₂. In another embodiment, X₂ of compound XXXIV is C(O). In anotherembodiment, Z of compound XXXIV is CN and Y is CF₃. In anotherembodiment, X₄ of compound XXXIV is O, Z is CN, Q is CN, R₁, R₂ and R₃are H, and Y is CF₃.

In another embodiment, this invention provides a compound of formulaXXXV:

In another embodiment, this invention provides a compound of formulaXXXVI:

In one embodiment, this invention provides a compound represented by thestructure of formula XXXVII:

wherein

X, X₂, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above in compoundXXXIV.

In another embodiment, X₄ of compound XXXVII is O. In anotherembodiment, X₂ of compound XXXVII is C(O). In another embodiment, X₂ ofcompound XXXVII is CH₂. In another embodiment, Q of compound XXXVII isCN. In another embodiment, Z of compound XXXVII is CN and Y is CF₃.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXVIII:

wherein X, X₂, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above incompound XXXIV.

In another embodiment, X₄ of compound XXXVIII is O. In anotherembodiment, X₂ of compound XXXVIII is C(O). In another embodiment, X₂ ofcompound XXXVIII is CH₂. In another embodiment, Q of compound XXXVIII isCN. In another embodiment, Z of compound XXXVIII is CN and Y is CF₃.

In one embodiment, this invention provides a compound of formula I,wherein P is formula I, X₁ and X₅ together with X₂ to which X₁ and X₅are attached form a saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring;

-   -   wherein    -   if P is formula II, X is C, X₃ is CH₂, X₄ is O, or NH, R₁, R₂        and R₃ are H, and X₅ and X₁ forms a 5 membered ring, an        oxazolidine-2-one then Q is not halogen, or H.

In one embodiment, this invention provides a compound of formula I,wherein P is formula II, X₁ and X₅ together with X₂ to which X₁ and X₅are attached form a saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring;

-   -   wherein    -   if P is formula II, X is C, X₃ is CH₂, X₄ is O, or NH, R₁, R₂        and R₃ are H, and X₅ and X₁ forms a 5 membered ring, an        oxazolidine-2-one then Q is not halogen, or H;    -   or    -   if P is formula II, R₃ is H, X and W are C, X₁ and X₅ together        with X₂ to which X₁ and X₅ are attached form a oxazolidinedione,        R is alkyl, X₃ is CH₂ and X₄ is O, NH, S, SO₂, or CH₂, then Q is        not an halide.

In another embodiment said saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring is pyrrolidine, piperidine,morpholine, succinimide, oxazolidine, oxazolidinedione or oxazolidinone.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIX:

-   -   wherein:    -   X is C or N; W is C or N;    -   G is O, NH, NC₁₋₄alkyl, NC₁₋₄acyl, S, CHC₁₋₄alkyl, CHC₁₋₄acyl,        C(C₁₋₄acyl)₂, C(C₁₋₄alkyl)₂ or (CH₂)_(n), where n is 1-3;    -   T is S or O;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH) [CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br;    -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl; R₃ is H,        C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula XXXIX:

-   -   wherein:    -   X is C or N; W is C or N;    -   G is O, NH, NC₁₋₄alkyl, NC₁₋₄acyl, S, CHC₁₋₄alkyl, CHC₁₋₄acyl,        C(C₁₋₄acyl)₂, C(C₁₋₄alkyl)₂ or (CH₂)_(n), where n is 1-3;    -   T is S or O;    -   X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,        C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],        PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond;    -   Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br;    -   Y is H, C₁₋₄alkyl, CF₃, NO₂,CN, F, Cl, I or Br;    -   Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl, C₂₋₆alkynyl,        C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,        NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,        NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],        O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or        O—[CH₂CH₂N(CH₃)₂];    -   R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl);    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;    -   R₃ is H, C₁₋₄alkyl, halide, CN or NO₂;    -   R′ is NH₂, OH or CH₃; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide; wherein    -   if R₃ is H, X and Ware C, G is O, T is O, R is alkyl, X₃ is CH₂        and X₄ is O, NH, S, SO₂, or CH₂, then Q is not an halide.

In one embodiment, this invention provides a compound of formula XL:

In one embodiment, this invention provides a compound of formula XLI:

In one embodiment, this invention provides a compound of formula XLII:

wherein X, X₄, Z, Y, Q, R₁, R₂ and R₃ are as described above in compoundXXXIX.

In one embodiment, this invention provides a compound of formula XLIII:

In one embodiment, this invention provides a compound of formula XLIV:

-   -   wherein:    -   X, X₄, R, R₁, R₂, R₃, Z, Y and Q are as described above in        compound XXXIXV;    -   wherein    -   if X is C, X₄ is O, NH, or S, R₁, R₂ and R₃ are H and R is H        then Q is not halogen, H or CN.

In one embodiment, this invention provides a compound represented by thestructure of formula XLV:

-   -   wherein X₄ is as described above in compound XXXIX.

In one embodiment, this invention provides a compound represented by thestructure of formula XLVI:

In one embodiment, this invention provides a compound represented by thestructure of formula XLVII:

-   -   wherein    -   X is N or CH;    -   Z is H, CN, NO₂, NHC(O)CH₃, CH₃, F, Cl, I or Br;    -   Y is H, CH₃, CF₃, CN, F, Cl, I or Br;    -   Q is H, O—(CH₂)₂CH(CH₃)₂ or O—(CH₂)₂N(CH₃)₂;    -   R₁ is H, OH, F, Cl, Br or I;    -   R₂ is benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,        CH₂—O-p-cyanophenyl, CH═CH—O-p-cyanophenyl;    -   R₃ is H, CH₃, halide, CN or NO₂;    -   R₄ and R₅ are independently are H, CH₃, halide, OH, C₁₋₄alkyl,        C₁₋₆cycloalkyl, halo-C₁₋₄alkyl, phenyl, aryl, heterocyclic, or        hydroxy-C₁₋₄alkyl; and    -   R₆ is CN, NO₂, NHC(O)CH₃ or halide.

In one embodiment, this invention provides a compound represented by thestructure of formula XLVIII:

In one embodiment, this invention provides a compound represented by thestructure of formula XLIX:

In one embodiment, this invention provides a compound represented by thestructure of formula L:

In one embodiment, this invention provides a compound represented by thestructure of formula LI:

In one embodiment, this invention provides a compound represented by thestructure of formula LII:

In another embodiment, this invention provides a pharmaceuticallyacceptable salt of the compound of formula (I). In another embodiment,this invention provides a pharmaceutical product of the compound offormula (I). In another embodiment, this invention provides a hydrate ofthe compound of formula (I). In another embodiment, this inventionprovides an N-oxide of the compound of formula (I). In anotherembodiment, this invention provides a polymorph of the compound offormula (I). In another embodiment, this invention provides a crystal ofthe compound of formula (I). In another embodiment, this inventionprovides a combination of any of a metabolite, isomer, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,hydrate, N-oxide of the compound of formula (I).

In some embodiments, the term “isomer” includes, but is not limited to,optical isomers and analogs, structural isomers and analogs,conformational isomers and analogs, and the like. In one embodiment, theterm “isomer” is meant to encompass optical isomers of the describedcompounds. It will be appreciated by those skilled in the art that thecompounds of the present invention contain at least one chiral center.Accordingly, the compounds used in the methods of the present inventionmay exist in, and be isolated in, optically-active or racemic forms.Some compounds may also exhibit polymorphism. It is to be understoodthat the present invention encompasses any racemic, optically-active,polymorphic, or stereoisomeric form, or mixtures thereof, which formpossesses properties useful in the treatment of androgen-relatedconditions described herein. In one embodiment, the compounds are thepure (R)-isomers. In another embodiment, the compounds are the pure(S)-isomers. In another embodiment, the SARMs are a mixture of the (R)and the (S) isomers. In another embodiment, the SARMs are a racemicmixture comprising an equal amount of the (R) and the (S) isomers. It iswell known in the art how to prepare optically-active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

In another embodiment, the compounds of this invention are a mixture ofthe (R) and the (S) isomers. In another embodiment, the mixturecomprises 60% of the (R) isomer and 40% of the (S) isomer. In anotherembodiment, the mixture comprises 40% of the (R) isomer and 60% of the(S) isomer. In another embodiment, the mixture comprises 70% of the (R)isomer and 30% of the (S) isomer. In another embodiment, the mixturecomprises 30% of the (R) isomer and 70% of the (S) isomer. In anotherembodiment, the mixture comprises 80% of the (R) isomer and 20% of the(S) isomer. In another embodiment, the mixture comprises 20% of the (R)isomer and 80% of the (S) isomer. In another embodiment, the mixturecomprises 90% of the (R) isomer and 10% of the (S) isomer. In anotherembodiment, the mixture comprises 10% of the (R) isomer and 90% of the(S) isomer.

In one embodiment, the compounds of this invention are SARMs. In oneembodiment, the compounds of this invention bind a nuclear hormonereceptor, such as, for example, the estrogen receptor, the progesteronereceptor, or the glucocorticoid receptor.

The invention includes “pharmaceutically acceptable salts” of thecompounds of this invention, which may be produced, by reaction of acompound of this invention with an acid or base.

Suitable pharmaceutically-acceptable salts of amines of Formula I may beprepared from an inorganic acid or from an organic acid. In oneembodiment, examples of inorganic salts of amines are bisulfates,borates, bromides, chlorides, hemisulfates, hydrobromates,hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates),iodates, iodides, isothionates, nitrates, persulfates, phosphates,sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates,arylsulfonates, halogen substituted alkylsulfonates, halogen substitutedarylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic salts of amines comprisealiphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areacetates, arginines, aspartates, ascorbates, adipates, anthranilate,alkane carboxylates, substituted alkane carboxylates, alginates,benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates,bitartrates, carboxylates, citrates, camphorates, camphorsulfonates,cyclohexylsulfamates, cyclopentanepropionates, calcium edetates,camsylates, carbonates, clavulanates, cinnamates, dicarboxylates,digluconates, dodecylsulfonates, dihydrochlorides, decanoates,enanthuates, ethanesulfonates, edetates, edisylates, estolates,esylates, fumarates, formates, fluorides, galacturonates, gluconates,glutamates, glycolates, glucorates, glucoheptanoates, glycerophosphates,gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates,hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates,hydroxybenzoates, hydroxynaphthoate, hydrofluorate, lactates,lactobionates, laurates, malates, maleates,methylenebis(beta-oxynaphthoate), malonates, mandelates, mesylates,methane sulfonates, methylbromides, methylnitrates, methylsulfonates,monopotassium maleates, mucates, monocarboxylates,naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, napsylates,N-methylglucamines, oxalates, octanoates, oleates, pamoates,phenylacetates, picrates, phenylbenzoates, pivalates, propionates,phthalates, pectinates, phenylpropionates, palmitates, pantothenates,polygalacturates, pyruvates, quinates, salicylates, succinates,stearates, sulfanilates, subacetates, tartrates, theophyllineacetates,p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates,tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates,undecanoates or valerates.

In one embodiment, examples of inorganic salts of carboxylic acids orphenols comprise ammonium, alkali metals to include lithium, sodium,potassium, cesium; alkaline earth metals to include calcium, magnesium,aluminum; zinc, barium, chlorines or quaternary ammoniums.

In another embodiment, examples of organic salts of carboxylic acids orphenols comprise arginine, organic amines to include aliphatic organicamines, alicyclic organic amines, aromatic organic amines, benzathines,t-butylamines, benethamines (N-benzylphenethylamine),dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines,ethylenediamines, hydrabamines, imidazoles, lysines, methylamines,meglamines, N-methyl-D-glucamines, N,N′-dibenzylethylenediamines,nicotinamides, organic amines, ornithines, pyridines, picolies,piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines,triethanolamines, trimethylamines, tromethamines or ureas.

In one embodiment, the salts may be formed by conventional means, suchas by reacting the free base or free acid form of the product with oneor more equivalents of the appropriate acid or base in a solvent ormedium in which the salt is insoluble or in a solvent such as water,which is removed in vacuo or by freeze drying or by exchanging the ionsof a existing salt for another ion or suitable ion-exchange resin.

In one embodiment, the invention also includes N-oxides of the aminosubstituents of the compounds described herein. Also, esters of thephenolic compounds can be made with aliphatic and aromatic carboxylicacids, for example, acetic acid and benzoic acid esters.

This invention provides derivatives of the compounds. In one embodiment,“derivatives” includes but is not limited to ether derivatives, acidderivatives, amide derivatives, ester derivatives and the like. Inanother embodiment, this invention further includes hydrates of thecompounds.

In one embodiment, “hydrate” includes but is not limited to hemihydrate,monohydrate, dihydrate, trihydrate and the like.

This invention provides, in other embodiments, metabolites of thecompounds. In one embodiment, “metabolite” means any substance producedfrom another substance by metabolism or a metabolic process.

This invention provides, in other embodiments, pharmaceutical productsof the compounds. The term “pharmaceutical product” refers, in otherembodiments, to a composition suitable for pharmaceutical use(pharmaceutical composition), for example, as described herein.

An “alkyl” group refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-12 carbons. In anotherembodiment, the alkyl group has 1-7 carbons. In another embodiment, thealkyl group has 1-6 carbons. In another embodiment, the alkyl group has1-4 carbons. The alkyl group may be unsubstituted or substituted by oneor more groups selected from halogen, hydroxy, alkoxy carbonyl, amido,alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl. In one embodiment, the alkyl group is CH₃.

An “alkenyl” group refers, in another embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bond. The alkenyl group may have one doublebond, two double bonds, three double bonds etc. Examples of alkenylgroups are ethenyl, propenyl, butenyl, cyclohexenyl etc. In oneembodiment, the alkylene group has 1-12 carbons. In another embodiment,the alkylene group has 1-7 carbons. In another embodiment, the alkylenegroup has 1-6 carbons. In another embodiment, the alkylene group has 1-4carbons. The alkenyl group may be unsubstituted or substituted by one ormore groups selected from halogen, hydroxy, alkoxy carbonyl, amido,alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino,carboxyl, thio and thioalkyl.

A “haloalkyl” group refers to an alkyl group as defined above, which issubstituted by one or more halogen atoms, in one embodiment by F, inanother embodiment by Cl, in another embodiment by Br, in anotherembodiment by I.

An “aryl” group refers to an aromatic group having at least onecarbocyclic aromatic group or heterocyclic aromatic group, which may beunsubstituted or substituted by one or more groups selected fromhalogen, haloalkyl, hydroxy, alkoxy, carbonyl, amido, alkylamido,dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio orthioalkyl. Nonlimiting examples of aryl rings are phenyl, naphthyl,pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl,furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. Inone embodiment, the aryl group is a 4-8 membered ring. In anotherembodiment, the aryl group is a 4-12 membered ring(s). In anotherembodiment, the aryl group is a 6 membered ring. In another embodiment,the aryl group is a 5 membered ring. In another embodiment, the arylgroup is 2-4 fused ring system.

A “hydroxyl” group refers to an OH group. It is understood by a personskilled in the art that when T is OR, R is not OH.

In one embodiment, the term “halogen refers to in one embodiment to F,in another embodiment to Cl, in another embodiment to Br, in anotherembodiment to I. In one embodiment, separation of the optically-active(R) isomer or (S) enantiomer, from the racemic compounds of thisinvention comprises crystallization techniques. In another embodiment,the crystallization techniques include differential crystallization ofenantiomers. In another embodiment, the crystallization techniquesinclude differential crystallization of diastereomeric salts (tartaricsalts or quinine salts). In another embodiment, the crystallizationtechniques include differential crystallization of chiral auxiliaryderivatives (menthol esters, etc). In another embodiment, separation ofthe optically-active (R) isomer or (S) enantiomer, from the racemiccompounds of this invention comprises reacting the racemate mixture withanother chiral group, forming of a diastereomeric mixture followed byseparation of the diastereomers and removing the additional chiral groupto obtain pure enantiomers. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic mixturesof compounds of this invention comprises chiral synthesis. In anotherembodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic mixture of the compounds of this inventioncomprises biological resolution. In another embodiment, separation ofthe optically-active (R) isomer or (S) enantiomer, from the racemicmixture of the compounds of this invention comprises enzymaticresolution. In another embodiment, separation of the optically-active(R) isomer or (S) enantiomer, from the racemic mixture of the compoundsof this invention comprises chromatographic separation using a chiralstationary phase. In another embodiment, separation of theoptically-active (R) isomer or (S) enantiomer, from the racemic mixtureof the compounds of this invention comprises affinity chromatography. Inanother embodiment, separation of the optically-active (R) isomer or (S)enantiomer, from the racemic mixture of the compounds of this inventioncomprises capillary electrophoresis. In another embodiment, separationof the optically-active (R) isomer or (S) enantiomer, from the racemicmixture of the compounds of this invention comprises forming an estergroup of the hydroxyl group of the chiral carbon with anoptically-active acid, for example (−)-camphanic acid, separating thediastereomers esters, thus obtained, by fractional crystallization orpreferably, by flash-chromatography, and then hydrolyzing each separateester to the alcohol.

In another embodiment, the purity, and selectivity of an enantiomerobtained by the process of this invention, or by chiral separation of aracemic mixture of this invention can be determined by HPLC analysis.

In another embodiment, the process further comprises the step ofconverting the compound of formula I to its isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, N-oxide,hydrate or any combination thereof.

It is to be understood that the process may comprise any embodimentdescribed herein, as will be appropriate to produce a compound of acorresponding formula, as will be appreciated by one skilled in the art.

In some embodiments, the compounds as described herein are useful inpreventing and treating muscle wasting disorders, bone relateddisorders, and diabetes related disorders.

In some embodiments, the compounds as described herein are useful,either alone or as a composition, in males and females for the treatmentof a variety of hormone-related conditions, such as hypogonadism,sarcopenia, erectile dysfunction, lack of libido, osteoporosis andfertility. In some embodiments, the compounds as described herein areuseful in stimulating or promoting or restoring function to variousprocesses, which in turn result in the treatment of the conditions asherein described, including, inter alia, promoting erythropoiesis,osteogenesis, muscle growth, glucose uptake, insulin secretion, and/orpreventing lipidogenesis, clotting, insulin resistance, atherosclerosis,osteoclast activity, and others.

In one embodiment, the methods of this invention make use of thedescribed compound contacting or binding a receptor, and therebymediating the described effects. In some embodiments, the receptor is anuclear receptor, which in one embodiment, is an androgen receptor, orin another embodiment, is an estrogen receptor, or in anotherembodiment, is a progesterone receptor, or in another embodiment, is aglucocorticoid receptor. In some embodiments, the multitude of effectsmay occur simultaneously, as a function of binding to multiple receptorsin the subject. In some embodiments, the tissue selective effects of thecompounds as described herein provide for simultaneous action ondifferent target organs.

Pharmaceutical Compositions

In some embodiments, this invention provides methods of use whichcomprise administering a composition comprising the described compounds.As used herein, “pharmaceutical composition” means a “therapeuticallyeffective amount” of the active ingredient, i.e. the compound of FormulaI, together with a pharmaceutically acceptable carrier or diluent. A“therapeutically effective amount” as used herein refers to that amountwhich provides a therapeutic effect for a given condition andadministration regimen.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a subject.

The pharmaceutical compositions containing the compounds of thisinvention can be administered to a subject by any method known to aperson skilled in the art, such as orally, parenterally,intravascularly, paracancerally, transmucosally, transdermally,intramuscularly, intranasally, intravenously, intradermally,subcutaneously, sublingually, intraperitoneally, intraventricularly,intracranially, intravaginally, by inhalation, rectally, intratumorally,or by any means in which the recombinant virus/composition can bedelivered to tissue (e.g., needle or catheter). Alternatively, topicaladministration may be desired for application to mucosal cells, for skinor ocular application. Another method of administration is viaaspiration or aerosol formulation.

In one embodiment, the pharmaceutical compositions are administeredorally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid or a liquid preparation. Suitable solidoral formulations include tablets, capsules, pills, granules, pellets,powders, and the like. Suitable liquid oral formulations includesolutions, suspensions, dispersions, emulsions, oils and the like. Inone embodiment of the present invention, the SARM compounds areformulated in a capsule. In accordance with this embodiment, thecompositions of the present invention comprise in addition to a compoundof this invention and the inert carrier or diluent, a hard gelatincapsule.

In one embodiment, the micronized capsules comprise particles containinga compound of this invention, wherein the term “micronized” used hereinrefers to particles having a particle size of less than 100 microns, orin another embodiment, less than 60 microns, or in another embodiment,less than 36 microns, or in another embodiment, less than 16 microns, orin another embodiment, less than 10 microns, or in another embodiment,less than 6 microns.

Further, in another embodiment, the pharmaceutical compositions areadministered by intravenous, intraarterial, or intramuscular injectionof a liquid preparation. Suitable liquid formulations include solutions,suspensions, dispersions, emulsions, oils and the like. In oneembodiment, the pharmaceutical compositions are administeredintravenously, and are thus formulated in a form suitable forintravenous administration. In another embodiment, the pharmaceuticalcompositions are administered intraarterially, and are thus formulatedin a form suitable for intraarterial administration. In anotherembodiment, the pharmaceutical compositions are administeredintramuscularly, and are thus formulated in a form suitable forintramuscular administration.

Further, in another embodiment, the pharmaceutical compositions areadministered topically to body surfaces, and are thus formulated in aform suitable for topical administration. Suitable topical formulationsinclude gels, ointments, creams, lotions, drops and the like. Fortopical administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are prepared and applied as solutions, suspensions, oremulsions in a physiologically acceptable diluent with or without apharmaceutical carrier.

Further, in another embodiment, the pharmaceutical compositions areadministered as a suppository, for example a rectal suppository or aurethral suppository. Further, in another embodiment, the pharmaceuticalcompositions are administered by subcutaneous implantation of a pellet.In a further embodiment, the pellet provides for controlled release of acompound as herein described over a period of time. In a furtherembodiment, the pharmaceutical compositions are administeredintravaginally.

In another embodiment, the active compound can be delivered in avesicle, in particular a liposome (see Langer, Science 249:1627-1633(1990); Treat et al., in Liposomes in the Therapy of Infectious Diseaseand Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp.363-366 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid).

As used herein “pharmaceutically acceptable carriers or diluents” arewell known to those skilled in the art. The carrier or diluent may be asolid carrier or diluent for solid formulations, a liquid carrier ordiluent for liquid formulations, or mixtures thereof.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.microcrystalline cellulose), an acrylate (e.g. polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

In one embodiment, the compositions of this invention may include, acompound of this invention or any combination thereof, together with oneor more pharmaceutically acceptable excipients.

It is to be understood that this invention encompasses any embodiment ofa compound as described herein, which in some embodiments is referred toas “a compound of this invention”.

Suitable excipients and carriers may be, according to embodiments of theinvention, solid or liquid and the type is generally chosen based on thetype of administration being used. Liposomes may also be used to deliverthe composition. Examples of suitable solid carriers include lactose,sucrose, gelatin and agar. Oral dosage forms may contain suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquiddosage forms may contain, for example, suitable solvents, preservatives,emulsifying agents, suspending agents, diluents, sweeteners, thickeners,and melting agents. Parenteral and intravenous forms should also includeminerals and other materials to make them compatible with the type ofinjection or delivery system chosen. Of course, other excipients mayalso be used.

For liquid formulations, pharmaceutically acceptable carriers may beaqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, cyclodextrins,emulsions or suspensions, including saline and buffered media. Examplesof oils are those of petroleum, animal, vegetable, or synthetic origin,for example, peanut oil, soybean oil, mineral oil, olive oil, sunfloweroil, and fish-liver oil.

Parenteral vehicles (for subcutaneous, intravenous, intraarterial, orintramuscular injection) include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's and fixedoils. Intravenous vehicles include fluid and nutrient replenishers,electrolyte replenishers such as those based on Ringer's dextrose, andthe like. Examples are sterile liquids such as water and oils, with orwithout the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. In general, water, saline, aqueous dextrose andrelated sugar solutions, and glycols such as propylene glycols orpolyethylene glycol are preferred liquid carriers, particularly forinjectable solutions. Examples of oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,mineral oil, olive oil, sunflower oil, and fish-liver oil.

In addition, the compositions may further comprise binders (e.g. acacia,cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropyl methyl cellulose, povidone), disintegratingagents (e.g. cornstarch, potato starch, alginic acid, silicon dioxide,croscarmelose sodium, crospovidone, guar gum, sodium starch glycolate),buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and ionicstrength, additives such as albumin or gelatin to prevent adsorption tosurfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acidsalts), protease inhibitors, surfactants (e.g. sodium lauryl sulfate),permeation enhancers, solubilizing agents (e.g., cremophor, glycerol,polyethylene glycerol, benzalkonium chloride, benzyl benzoate,cyclodextrins, sobitan esters, stearic acids), anti-oxidants (e.g.,ascorbic acid, sodium metabisulfite, butylated hydroxyanisole),stabilizers (e.g. hydroxypropyl cellulose, hyroxypropylmethylcellulose), viscosity increasing agents (e.g. carbomer, colloidalsilicon dioxide, ethyl cellulose, guar gum), sweeteners (e.g. aspartame,citric acid), preservatives (e.g., Thimerosal, benzyl alcohol,parabens), coloring agents, lubricants (e.g. stearic acid, magnesiumstearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g.colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate,triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose,sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g. ethyl cellulose,acrylates, polymethacrylates), and/or adjuvants.

In one embodiment, the pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the compoundof this invention is released over a period of time afteradministration. Controlled or sustained release compositions includeformulation in lipophilic depots (e.g. fatty acids, waxes, oils). Inanother embodiment, the composition is an immediate release composition,i.e. a composition in which the entire amount of compound is releasedimmediately after administration.

In yet another embodiment, the pharmaceutical composition can bedelivered in a controlled release system. For example, the agent may beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit.Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:607 (1980);Saudek et al., N. Engl. J. Med. 321:674 (1989). In another embodiment,polymeric materials can be used. In yet another embodiment, a controlledrelease system can be placed in proximity to the therapeutic target,i.e., the brain, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 116-138 (1984). Other controlled release systems arediscussed in the review by Langer (Science 249:1627-1633 (1990).

The compositions may also include incorporation of the active materialinto or onto particulate preparations of polymeric compounds such aspolylactic acid, polglycolic acid, hydrogels, etc., or onto liposomes,microemulsions, micelles, unilamellar or multilamellar vesicles,erythrocyte ghosts, or spheroplasts. Such compositions will influencethe physical state, solubility, stability, rate of in vivo release, andrate of in vivo clearance.

Also comprehended by the invention are particulate compositions coatedwith polymers (e.g. poloxamers or poloxamines) and the compound coupledto antibodies directed against tissue-specific receptors, ligands orantigens or coupled to ligands of tissue-specific receptors.

Also comprehended by the invention are compounds modified by thecovalent attachment of water-soluble polymers such as polyethyleneglycol, copolymers of polyethylene glycol and polypropylene glycol,carboxymethyl cellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone or polyproline. The modified compounds are known toexhibit substantially longer half-lives in blood following intravenousinjection than do the corresponding unmodified compounds (Abuchowski etal., 1981; Newmark et al., 1982; and Katre et al., 1987). Suchmodifications may also increase the compound's solubility in aqueoussolution, eliminate aggregation, enhance the physical and chemicalstability of the compound, and greatly reduce the immunogenicity andreactivity of the compound. As a result, the desired in vivo biologicalactivity may be achieved by the administration of such polymer-compoundabducts less frequently or in lower doses than with the unmodifiedcompound.

The preparation of pharmaceutical compositions which contain an activecomponent is well understood in the art, for example by mixing,granulating, or tablet-forming processes. The active therapeuticingredient is often mixed with excipients which are pharmaceuticallyacceptable and compatible with the active ingredient. For oraladministration, the compounds of this invention or their physiologicallytolerated derivatives such as salts, esters, N-oxides, and the like aremixed with additives customary for this purpose, such as vehicles,stabilizers, or inert diluents, and converted by customary methods intosuitable forms for administration, such as tablets, coated tablets, hardor soft gelatin capsules, aqueous, alcoholic or oily solutions. Forparenteral administration, the compounds of this invention or theirphysiologically tolerated derivatives such as salts, esters, N-oxides,and the like are converted into a solution, suspension, or emulsion, ifdesired with the substances customary and suitable for this purpose, forexample, solubilizers or other.

An active component can be formulated into the composition asneutralized pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include the acid addition salts (formed with the freeamino groups of the polypeptide or antibody molecule), which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed from the free carboxyl groups can also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

For use in medicine, the salts of the compound will be pharmaceuticallyacceptable salts. Other salts may, however, be useful in the preparationof the compounds according to the invention or of their pharmaceuticallyacceptable salts. Suitable pharmaceutically acceptable salts of thecompounds of this invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound according to theinvention with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid,maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid,citric acid, tartaric acid, carbonic acid or phosphoric acid.

In one embodiment, this invention provides pharmaceutical compositionscomprising a compound of this invention. In one embodiment, suchcompositions are useful for oral testosterone replacement therapy.

In one embodiment, this invention also provides a composition comprisingtwo or more compounds of this invention, or polymorphs, isomers,hydrates, salts, N-oxides, etc., thereof. The present invention alsorelates to compositions and a pharmaceutical compositions whichcomprises a compound of this invention alone or in combination with aprogestin or estrogen, or in another embodiment, chemotherapeuticcompound, osteogenic or myogenic compound, or other agents suitable forthe applications as herein described. In one embodiment, thecompositions of this invention will comprise a suitable carrier, diluentor salt.

In one embodiment, the methods of this invention may compriseadministration of a compound of formula I of this invention at variousdosages. In one embodiment, the compound of this invention isadministered at a dosage of 0.1-200 mg per day. In one embodiment, thecompound of this invention is administered at a dose of 0.1-10 mg, or inanother embodiment, 0.1-26 mg, or in another embodiment, 0.1-60 mg, orin another embodiment, 0.3-16 mg, or in another embodiment, 0.3-30 mg,or in another embodiment, 0.6-26 mg, or in another embodiment, 0.6-60mg, or in another embodiment, 0.76-16 mg, or in another embodiment,0.76-60 mg, or in another embodiment, 1-6 mg, or in another embodiment,1-20 mg, or in another embodiment, 3-16 mg, or in another embodiment,30-60 mg, or in another embodiment, 30-76 mg, or in another embodiment,100-2000 mg.

In one embodiment, the methods of this invention may compriseadministration of a compound of formula I of this invention at variousdosages. In one embodiment, the compound of this invention isadministered at a dosage of 1 mg. In another embodiment the compound ofthis invention is administered at a dosage of 3 mg, 6 mg, 10 mg, 16 mg,20 mg, 26 mg, 30 mg, 36 mg, 40 mg, 46 mg, 50 mg, 56 mg, 60 mg, 66 mg, 70mg, 76 mg, 80 mg, 86 mg, 90 mg, 96 mg or 100 mg.

In one embodiment, the present invention provides methods of usecomprising the administration of a pharmaceutical composition comprisinga) any embodiment of a compound as described herein; and b) apharmaceutically acceptable carrier or diluent; which is to beunderstood to include an analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, N-oxide, hydrate or any combinationthereof of a compound as herein described, and may comprise compounds offormula I.

In some embodiments, the present invention provides methods of use of apharmaceutical composition comprising a) any embodiment of the compoundsas described herein, including an analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate thereof or any combination thereof; b) apharmaceutically acceptable carrier or diluent; c) a flow-aid; and d) alubricant.

In another embodiment, the present invention provides methods of use ofa pharmaceutical composition comprising a) any embodiment of thecompounds as described herein, including an analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,N-oxide, hydrate thereof or any combination thereof; b) lactosemonohydrate; c) microcrystalline cellulose; d) magnesium stearate; ande) colloidal silicon dioxide.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention, as described herein. In one embodiment, use of acompound of this invention or a composition comprising the same, willhave utility in inhibiting, suppressing, enhancing or stimulating adesired response in a subject, as will be understood by one skilled inthe art. In another embodiment, the compositions may further compriseadditional active ingredients, whose activity is useful for theparticular application for which the compound of this invention is beingadministered.

In some embodiments, the methods of this invention make use ofcompositions comprising compounds of this invention, which offer theadvantage that the compounds are nonsteroidal ligands for the androgenreceptor, and exhibit anabolic activity in vivo. According to thisaspect, such compounds are unaccompanied by serious side effects,provide convenient modes of administration, and lower production costsand are orally bioavailable, lack significant cross-reactivity withother undesired steroid receptors, and may possess long biologicalhalf-lives.

For administration to mammals, and particularly humans, it is expectedthat the physician will determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In one embodiment, the compositions for administration may be sterilesolutions, or in other embodiments, aqueous or non-aqueous, suspensionsor emulsions. In one embodiment, the compositions may comprise propyleneglycol, polyethylene glycol, injectable organic esters, for exampleethyl oleate, or cyclodextrins. In another embodiment, compositions mayalso comprise wetting, emulsifying and/or dispersing agents. In anotherembodiment, the compositions may also comprise sterile water or anyother sterile injectable medium.

In one embodiment, the invention provides compounds and compositions,including any embodiment described herein, for use in any of the methodsof this invention. In one embodiment, use of a compound of thisinvention or a composition comprising the same, will have utility ininhibiting, suppressing, enhancing or stimulating a desired response ina subject, as will be understood by one skilled in the art. In anotherembodiment, the compositions may further comprise additional activeingredients, whose activity is useful for the particular application forwhich the compound of this invention is being administered.

In some embodiments, the compositions will further comprise a5alpha-reductase inhibitors (5ARI), a SARM or SARMs, a selectiveestrogen receptor modulator (SERM), an aromatase inhibitor, such as butnot limited to anastrazole, exemestane, or letrozole; a GnRH agonist orantagonist, a steroidal or nonsteroidal GR ligand, a steroidal ornonsteroidal PR ligand, a steroidal or nonsteroidal AR antagonist, a17-aldoketoreductase inhibitor or 17β-hydroxysteroid dehydrogenaseinhibitor. Such compositions may be used, in some embodiments, fortreating a hormone dependent condition, such as, for example,infertility, neoplasia of a hormone-responsive cancer, for example, agonadal cancer, or a urogenital cancer.

In some embodiments, the composition will comprise the compounds asdescribed herein, as well as another therapeutic compound, includinginter alia, a 5ARI such as finasteride, dutasteride, izonsteride; otherSARMs, such as, RU-58642, RU-56279, WS9761 A and B, RU-59063, RU-58841,bexlosteride, LG-2293, L-245976, LG-121071, LG-121091, LG-121104,LGD-2226, LGD-2941, LGD-3305, YM-92088, YM-175735, LGD-1331, BMS-357597,BMS-391197, S-40503, BMS-482-404, EM-4283, EM-4977, BMS-564929,BMS-391197, BMS-434588, BMS-487745, BMS-501949, SA-766, YM-92088,YM-580, LG-123303, LG-123129, PMCol, YM-175735, BMS-591305, BMS-591309,BMS-665139, BMS-665539, CE-590, 116BG33, 154BG31, arcarine, ACP-105;SERMs, such as tamoxifene, 4-hydroxytamoxifene, idoxifene, toremifene,ospemifene, droloxifene, raloxifene, arzoxifene, bazedoxifene, PPT(1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole), DPN(diarylpropionitrile), lasofoxifene, pipendoxifene, EM-800, EM-652,nafoxidine, zindoxifene, tesmilifene, miproxifene phosphate, RU 58,688,EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, diethylstibestrol,coumestrol, genistein, GW5638, LY353581, zuclomiphene, enclomiphene,delmadinone acetate, DPPE,(N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [18F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-10,CT-102, VG-101; GnRH agonists or antagonists, such as, leuprolide,goserelin, triptorelin, alfaprostol, histrelin, detirelix, ganirelix,antide iturelix, cetrorelix, ramorelix, ganirelix, antarelix, teverelix,abarelix, ozarelix, sufugolix, prazarelix, degarelix, NBI-56418,TAK-810, acyline; FSH agonist/antagonist, LH agonist/antagonists,aromatase inhibitors, such as, letrozole, anastrazole, atamestane,fadrozole, minamestane, exemestane, plomestane, liarozole, NKS-01,vorozole, YM-511, finrozole, 4-hydroxyandrostenedione, aminogluethimide,rogletimide; Steroidal or nonsteroidal glucocorticoid receptor ligands,such as, ZK-216348, ZK-243149, ZK-243185, LGD-5552, mifepristone,RPR-106541, ORG-34517, GW-215864X, Sesquicillin, CP-472555, CP-394531,A-222977, AL-438, A-216054, A-276575, CP-394531, CP-409069, UGR-07;Steroidal or nonsteroidal progesterone receptor ligands; Steroidal ornonsteroidal AR antagonists such as flutamide, hydroxyflutamide,bicalutamide, nilutamide, hydroxysteroid dehydrogenase inhibitors, PPARαligand such as bezafibrate, fenofibrate, gemfibrozil; PPARγ ligands suchas darglitazone, pioglitazone, rosiglitazone, isaglitazone,rivoglitazone, netoglitazone; Dual acting PPAR ligands, such asnaveglitazar, farglitazar, tesaglitazar, ragaglitazar, oxeglitazar,PN-2034, PPAR δ; 17-ketoreductase inhibitors, 3β-DHΔ4,6-isomeraseinhibitors, 3β-DHΔ4,5-isomerase inhibitors, 17,20 desmolase inhibitors,p450c 17 inhibitors, p450ssc inhibitors, 17,20-lyase inhibitors, orcombinations thereof.

It is to be understood that any of the above means, timings, routes, orcombinations thereof, of administration of two or more agents is to beconsidered as being encompassed by the phrase “administered incombination”, as described herein.

In one embodiment, this invention provides for the treatment,prevention, suppression or inhibition of, or the reduction of the riskof developing a skeletal-related event (SRE), such as bone fractures,surgery of the bone, radiation of the bone, spinal cord compression, newbone metastasis, bone loss, or a combination thereof in a subject withcancer, comprising administering to the a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof. The invention relates, inter alia to treatment ofan SRE with the compound of formula (I) in a subject with prostatecancer undergoing or having undergone androgen deprivation therapy(ADT).

In one embodiment, the skeletal-related events treated using the methodsprovided herein and/or utilizing the compositions provided herein, arefractures, which in one embodiment, are pathological fractures,non-traumatic fractures, vertebral fracture, non-vertebral fractures,morphometric fractures, or a combination thereof. In some embodiments,fractures may be simple, compound, transverse, greenstick, or comminutedfractures. In one embodiment, fractures may be to any bone in the body,which in one embodiment, is a fracture in any one or more bones of thearm, wrist, hand, finger, leg, ankle, foot, toe, hip, collar bone, or acombination thereof.

In another embodiment, the methods and/or compositions provided herein,are effective in treatment, prevention, suppression, inhibition orreduction of the risk of skeletal-related events such as pathologicfractures, spinal cord compression, hypercalcemia, bone-related pain, ortheir combination.

In another embodiment, the skeletal-related events sought to be treatedusing the methods provided herein and/or utilizing the compositionsprovided herein, comprise the necessity for bone surgery and/or boneradiation, which in some embodiments, is for the treatment of painresulting in one embodiment from bone damage, or nerve compression. Inanother embodiment, the skeletal-related events sought to be treatedusing the methods provided herein and/or utilizing the compositionsprovided herein, comprise spinal cord compression, or the necessity forchanges in antineoplastic therapy, including changes in hormonaltherapy, in a subject. In some embodiments, skeletal-related eventssought to be treated using the methods provided herein and/or utilizingthe compositions provided herein, comprise treating, suppressing,preventing, reducing the incidence of, or delaying progression orseverity of bone metastases, or bone loss. In one embodiment, bone lossmay comprise osteoporosis, osteopenia, or a combination thereof. In oneembodiment, skeletal-related events may comprise any combination of theembodiments listed herein.

In one embodiment, the methods provided herein and/or utilizing thecompositions provided herein, are effective in reducing metastases tothe bone, such as in terms of number of foci, the size of foci, or acombination thereof. According to this aspect of the invention and inone embodiment, provided herein is a method of preventing or inhibitingcancer metastasis to bone in a subject, comprising the step ofadministering to the subject a composition comprising toremifene,raloxifene, tamoxifen or an analogue, functional derivative, metaboliteor a combination thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, such metabolites may comprise ospemifene, fispemifeneor their combination. In one embodiment, the cancer is prostate cancer.

In one embodiment, the skeletal-related events are a result of cancertherapy. In one embodiment, the skeletal-related events are a result ofhormone deprivation therapy, while in another embodiment, they are aproduct of androgen deprivation therapy (ADT).

In one embodiment, the compounds of this invention are useful inprevention or reversal of androgen-deprivation therapy (ADT) inducedside effects such as reduced muscle mass, reduced muscle strength,frailty, hypogonadism, osteoporosis, osteopenia, decreased BMD and/ordecreased bone mass.

In males, while the natural decline in sex-hormones at maturity (directdecline in androgens as well as lower levels of estrogens derived fromperipheral aromatization of androgens) is associated with the frailty ofbones, this effect is more pronounced in males who have undergoneandrogen deprivation therapy.

In some embodiments, any of the compositions of this invention willcomprise a compound of formula I, in any form or embodiment as describedherein. In some embodiments, any of the compositions of this inventionwill consist of a compound of formula I, in any form or embodiment asdescribed herein. In some embodiments, of the compositions of thisinvention will consist essentially of a compound of I, in any form orembodiment as described herein. In some embodiments, the term “comprise”refers to the inclusion of the indicated active agent, such as thecompound of formula I, as well as inclusion of other active agents, andpharmaceutically acceptable carriers, excipients, emollients,stabilizers, etc., as are known in the pharmaceutical industry. In someembodiments, the term “consisting essentially of” refers to acomposition, whose only active ingredient is the indicated activeingredient, however, other compounds may be included which are forstabilizing, preserving, etc. the formulation, but are not involveddirectly in the therapeutic effect of the indicated active ingredient.In some embodiments, the term “consisting essentially of” may refer tocomponents which facilitate the release of the active ingredient. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

In one embodiment, the present invention provides combined preparations.In one embodiment, the term “a combined preparation” defines especiallya “kit of parts” in the sense that the combination partners as definedabove can be dosed independently or by use of different fixedcombinations with distinguished amounts of the combination partnersi.e., simultaneously, concurrently, separately or sequentially. In someembodiments, the parts of the kit of parts can then, e.g., beadministered simultaneously or chronologically staggered, that is atdifferent time points and with equal or different time intervals for anypart of the kit of parts. The ratio of the total amounts of thecombination partners, in some embodiments, can be administered in thecombined preparation. In one embodiment, the combined preparation can bevaried, e.g., in order to cope with the needs of a patient subpopulationto be treated or the needs of the single patient which different needscan be due to a particular disease, severity of a disease, age, sex, orbody weight as can be readily made by a person skilled in the art.

It is to be understood that this invention is directed to compositionsand combined therapies as described herein, for any disease, disorder orcondition, as appropriate, as will be appreciated by one skilled in theart. Certain applications of such compositions and combined therapieshave been described hereinabove, for specific diseases, disorders andconditions, representing embodiments of this invention, and methods oftreating such diseases, disorders and conditions in a subject byadministering a compound as herein described, alone or as part of thecombined therapy or using the compositions of this invention representadditional embodiments of this invention.

Biological Activity of Selective Androgen Modulator Compounds

The compounds of this invention may be useful, in some embodiments, fororal testosterone replacement therapy. In other embodiments,appropriately substituted compounds are useful for a) malecontraception; b) treatment of a variety of hormone-related conditions,for example conditions associated with ADAM, such as fatigue,depression, decreased libido, sexual dysfunction, erectile dysfunction,hypogonadism, osteoporosis, hair loss, obesity, sarcopenia, osteopenia,benign prostate hyperplasia, and alterations in mood and cognition; c)treatment of conditions associated with ADIF, such as sexualdysfunction, decreased sexual libido, hypogonadism, sarcopenia,osteopenia, osteoporosis, alterations in cognition and mood, depression,anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancerand ovarian cancer; d) treatment and/or prevention of chronic muscularwasting; e) treatment of prostate cancer, imaging of prostate cancer;decreasing the incidence of, halting or causing a regression of prostatecancer; f) treatment of diabetes type I; g) treatment of diabetes typeII; h) suppressing or inhibiting or reducing the incidence of diabetesi) treatment of glucose intolerance; j) treatment of hyperinsulinemia;k) treatment of insulin resistance 1) treatment of diabetic nephropathy;m) treatment of diabetic neuropathy; n) treatment of diabeticretinopathy; o) treatment of fatty liver condition; p) treatment ofcachexia; q) oral androgen replacement and/or other clinical therapeuticand/or diagnostic areas, including any embodiment of what is encompassedby the term “treating” as described herein.

In some embodiments, the compounds of this invention possess in vivotissue selective androgenic and anabolic activity, which is accordinglyutilized for particular applications, as will be appreciated by oneskilled in the art.

In one embodiment, this invention provides: a) a method of treating asubject having a muscle wasting disorder; b) a method of treating asubject suffering from malnutrition; c) a method of treating abone-related disorder in a subject; d) a method of increasing a bonemass in a subject; e) a method of improving the lipid profile in asubject; f) a method of treating atherosclerosis and its associateddiseases; g) a method of improving dexterity and movement in a subject;h) a method of treating a subject having dwarfism; i) a method oftreating a subject having dysmenorrhea; j) a method of treating asubject having dysparunia; k) a method of treating a subject havingdysspermatogenic sterility; comprising the step of administering to saidsubject a compound of formula I and/or an analog, derivative, isomer,metabolite, pharmaceutically acceptable salt, pharmaceutical product,hydrate, N-oxide, prodrug, polymorph, impurity or crystal of saidcompound, or any combination thereof.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications andtreating diseases in which the improvement of cognition, reduction ortreatment of depression, or other neuroprotective effects are desired.

In one embodiment, “Cognition” refers to the process of knowing,specifically the process of being aware, knowing, thinking, learning andjudging. Cognition is related to the fields of psychology, linguistics,computer science, neuroscience, mathematics, ethology and philosophy. Inone embodiment, “mood” refers to a temper or state of the mind. Ascontemplated herein, alterations mean any change for the positive ornegative, in cognition and/or mood.

In one embodiment, “depression” refers to an illness that involves thebody, mood and thoughts that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

In one embodiment, the methods of this invention are useful in asubject, which is a human. In another embodiment, the subject is amammal. In another embodiment the subject is an animal. In anotherembodiment the subject is an invertebrate. In another embodiment thesubject is a vertebrate.

In one embodiment, the subject is male. In another embodiment, thesubject is female. In some embodiments, while the methods as describedherein may be useful for treating either males or females, females mayrespond more advantageously to administration of certain compounds, forcertain methods, as described and exemplified herein.

In some embodiments, while the methods as described herein may be usefulfor treating either males or females, males may respond moreadvantageously to administration of certain compounds, for certainmethods, as described herein.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in ortreating hair loss, alopecia, androgenic alopecia, alopecia greata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring or alopecia induced by stress. Inone embodiment, “hair loss”, or “alopecia”, refers to baldness as in thevery common type of male-pattern baldness. Baldness typically beginswith patch hair loss on the scalp and sometimes progresses to completebaldness and even loss of body hair. Hair loss affects both males andfemales.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in, ortreating diseases or conditions associated with a subject having anemia.In one embodiment, “anemia” refers to the condition of having less thanthe normal number of red blood cells or less than the normal quantity ofhemoglobin in the blood, reduced hematocrit or reduced mean corpuscularvolume, or reduced corpuscular size. The oxygen-carrying capacity of theblood is decreased in anemia. In some embodiments, treating anemia mayalso refer herein to treating underlying factors resulting in anemia,such as for example: a) hemorrhage (bleeding); b) hemolysis (excessivedestruction of red blood cells); c) underproduction of red blood cells;and d) not enough normal hemoglobin. In some embodiments, treatinganemia in this invention refers to treating any form thereof, includingaplastic anemia, benzene poisoning, Fanconi anemia, hemolytic disease ofthe newborn, hereditary spherocytosis, iron deficiency anemia,osteoporosis, pernicious anemia, aplastic anemia, hemolytic anemia,sickle cell anemia, renal anemia, thalassemia, myelodysplastic syndrome,and a variety of bone marrow diseases.

In some embodiments, the compounds as described herein and/orcompositions comprising the same may be used for applications in and/ortreating diseases and/or conditions associated with problems with asubject's libido, or erectile dysfunction in a subject. In oneembodiment, “libido”, may refer to sexual desire.

In one embodiment, the term “erectile” refers to the ability to be erector upright. An erectile tissue is a tissue, which is capable of beinggreatly dilated and made rigid by the distension of the numerous bloodvessels, which it contains.

In another embodiment of the present invention, a method is provided forhormonal therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes contacting an androgenreceptor of a patient with a compound and/or a non steroidal agonist ofthe present invention and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, in anamount effective to bind the compound to the androgen receptor andeffect a change in an androgen-dependent condition.

In one embodiment of this invention, a method is provided for hormonereplacement therapy in a patient (i.e., one suffering from anandrogen-dependent condition) which includes administering a compound asherein described and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, hydrate, N-oxide or any combination thereof, to asubject, in an amount sufficient to effect a change in ahormone-dependent condition in the subject.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, comprising the methods of thepresent invention include those conditions which are associated withaging, hypogonadism, sarcopenia, diminished erythropoiesis,osteoporosis, and any other conditions dependent upon low androgen(e.g., testosterone) or estrogen levels.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, and comprising a method of theinvention, may comprise conditions characterized by elevated androgen orestrogen levels, including hirsutism, infertility, polycystic ovariansyndrome, endometrial carcinoma, breast cancer, male pattern baldness,prostate cancer, testicular cancer, and others, as will be known to oneskilled in the art. For such conditions, the subject may be administereda compound as herein described, alone or in combination with anothertherapeutic agent, as will be appreciated by one skilled in the art.

In one embodiment, this invention provides methods for the treatment ofa cancer in a subject, reduction of incidence or severity orpathogenesis of a cancer in a subject, delaying progression, prolongingremission or delaying onset of cancer in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, hydrate,N-oxide or any combination thereof. In some embodiments, such cancersare hormone-dependent or androgen receptor dependent tumors (malignantor benign) associated with reproductive tissue in males or females, suchas cancer of the prostate, ovary, breast, uterus, testicle, or others.

In some embodiments, this invention provides methods for the treatmentof a precancerous precursor or lesion in a subject, reduction ofincidence of precancerous precursors or lesions in a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, polymorph, crystal, impurity,hydrate, N-oxide or any combination thereof. In some embodiments, suchprecancerous precursors are androgen receptor dependent tumors found inhormone-responsive tissue or are associated with reproductive tissue inmales or females, such as in the prostate, ovary, breast, uterus,testicle, or others. In some embodiments, such precancerous precursorscomprise any local intraepithelial neoplasia, for example, of theprostate, the cervix, etc. In some embodiments, such methods are usefulin treating neoplasia or pre-neoplasia, dysplasia or hyperplasia in atissue, such as in reproductive tissue in males or females.

In one embodiment, this invention provides compounds, compositionsand/or methods of use thereof in treating benign prostate hyperplasia(BPH). “BPH (benign prostate hyperplasia)” is a nonmalignant enlargementof the prostate gland, and is the most common non-malignantproliferative abnormality found in any internal organ and the majorcause of morbidity in the adult male. BPH occurs in over 75% of men over50 years of age, reaching 88% prevalence by the ninth decade. BPHfrequently results in a gradual squeezing of the portion of the urethrawhich traverses the prostate (prostatic urethra). This causes patientsto experience a frequent urge to urinate because of incomplete emptyingof the bladder and urgency of urination. The obstruction of urinary flowcan also lead to a general lack of control over urination, includingdifficulty initiating urination when desired, as well as difficulty inpreventing urinary flow because of the inability to empty urine from thebladder, a condition known as overflow urinary incontinence, which canlead to urinary obstruction and to urinary failure.

In another embodiment of the present invention, the method for treatingbenign prostate hyperplasia (BPH) in a subject, comprises the step ofadministering to the subject a compound as herein described and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, polymorph, crystal, impurity, hydrate,N-oxide or any combination thereof, in an amount effective to treat BPHin the subject.

In some embodiments, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, or reducing pathogenesis of cachexia and/or cachexia associated withcancer in a subject. In another embodiment, the cancer compriseadrenocortical carcinoma, anal cancer, bladder cancer, brain tumor,brain stem glioma, brain tumor, cerebellar astrocytoma, cerebralastrocytoma, ependymoma, medulloblastoma, supratentorial primitiveneuroectodermal, pineal tumors, hypothalamic glioma, breast cancer,carcinoid tumor, carcinoma, cervical cancer, colon cancer, colorectalcancer, endometrial cancer, esophageal cancer, extrahepatic bile ductcancer, ewings family of tumors (Pnet), extracranial germ cell tumor,eye cancer, intraocular melanoma, gallbladder cancer, gastric cancer,germ cell tumor, extragonadal, gestational trophoblastic tumor, head andneck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngealcancer, leukemia, acute lymphoblastic leukemia, oral cavity cancer,liver cancer, lung cancer, non small cell lung cancer, small cell lungcancer, lymphoma, AIDS-related lymphoma, central nervous system(primary), lymphoma, cutaneous T-cell, lymphoma, Hodgkin's disease,non-Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cellcarcinoma, metasatic squamous carcinoma, multiple myeloma, plasma cellneoplasms, mycosis fungoides, myelodysplastic syndrome,myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma,oropharyngeal cancer, osteosarcoma, ovarian epithelial cancer, ovariangerm cell tumor, ovarian low malignant potential tumor, exocrinepancreatic cancer, islet cell carcinoma pancreatic cancer, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pheochromocytoma cancer, pituitary cancer, plasma cell neoplasm,prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell cancer,salivary gland cancer, Sezary syndrome, skin cancer, cutaneous T-celllymphoma, Kaposi's sarcoma, melanoma, small intestine cancer, softtissue sarcoma, soft tissue sarcoma, testicular cancer, thymoma,malignant, thyroid cancer, urethral cancer, uterine cancer, sarcoma,unusual cancer of childhood, vaginal cancer, vulvar cancer, Wilms'tumor, or any combination thereof.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of lung cancer.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of non small cell lung cancer.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of Hodgkin's disease, or in another embodiment,non-Hodgkin's disease.

In another embodiment, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, delaying the onset of colorectal cancer.

In some embodiments, this invention provides for the use of a compoundas herein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for treating reducing the severity of, reducing the incidenceof, or reducing pathogenesis of cancer. In another embodiment, thecancer comprises androgen AR dependent tumors (malignant or benign) suchas prostate cancer, breast cancer (male or female, operable orinoperable). In another embodiment the SARM compounds are an adjunct toADT for treating prostate cancer; bladder cancers; brain cancers; bonetumors, colon cancer, endometrial cancer, liver cancer, lung cancer,lymphatic cancer, kidney cancer, osteosarcoma cancer, ovarian cancer,pancreas cancer, penis cancer, skin cancer, thyroid cancer; and/orhormone-dependent cancers.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) treating a bone related disorder; b) preventing a bonerelated disorder; c) suppressing a bone related disorder; d) inhibitinga bone related disorder; e) increasing a strength of a bone of asubject; f) increasing a bone mass in a subject; g) use forosteoclastogenesis inhibition.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for a) accelerate bone repair; b) treating bone disorders; c)treating bone density loss; d) treating low bone mineral density (BMD);e) treating reduced bone mass; f) treating metabolic bone disease; g)promoting bone growth or regrowth; h) promoting bone restoration; i)promoting bone fracture repair; j) promoting bone remodeling; k)treating bone damage following reconstructive surgery including of theface, hip, or joints; I) enhancing of bone strength and function; m)increasing cortical bone mass; n) increasing trabecular connectivity.

In one embodiment, the bone related disorder is a genetic disorder, orin another embodiment, is induced as a result of a treatment regimen fora given disease. For example, and in one embodiment, the compounds asherein described are useful in treating a bone-related disorder thatarises as a result of cancer metastasis to bone, or in anotherembodiment, as a result of androgen-deprivation therapy, for example,given in response to prostate carcinogenesis in the subject.

In one embodiment, the bone-related disorder is osteoporosis. In anotherembodiment, the bone-related disorder is osteopenia. In anotherembodiment, the bone-related disorder is increased bone resorption. Inanother embodiment, the bone-related disorder is bone fracture. Inanother embodiment, the bone-related disorder is bone frailty.

In another embodiment, the bone-related disorder is a loss of bonemineral density (BMD). In another embodiment, the bone-related disorderis any combination of osteoporosis, osteopenia, increased boneresorption, bone fracture, bone frailty and loss of BMD. Each disorderrepresents a separate embodiment of the present invention.

“Osteoporosis” refers, in one embodiment, to a thinning of the boneswith reduction in bone mass due to depletion of calcium and boneprotein. In another embodiment, osteoporosis is a systemic skeletaldisease, characterized by low bone mass and deterioration of bonetissue, with a consequent increase in bone fragility and susceptibilityto fracture. In osteoporotic patients, bone strength is abnormal, in oneembodiment, with a resulting increase in the risk of fracture. Inanother embodiment, osteoporosis depletes both the calcium and theprotein collagen normally found in the bone, in one embodiment,resulting in either abnormal bone quality or decreased bone density. Inanother embodiment, bones that are affected by osteoporosis can fracturewith only a minor fall or injury that normally would not cause a bonefracture. The fracture can be, in one embodiment, either in the form ofcracking (as in a hip fracture) or collapsing (as in a compressionfracture of the spine). The spine, hips, and wrists are common areas ofosteoporosis-induced bone fractures, although fractures can also occurin other skeletal areas. Unchecked osteoporosis can lead, in anotherembodiment, to changes in posture, physical abnormality, and decreasedmobility.

In one embodiment, the osteoporosis results from androgen deprivation.In another embodiment, the osteoporosis follows androgen deprivation. Inanother embodiment, the osteoporosis is primary osteoporosis. In anotherembodiment, the osteoporosis is secondary osteoporosis. In anotherembodiment, the osteoporosis is postmenopausal osteoporosis. In anotherembodiment, the osteoporosis is juvenile osteoporosis. In anotherembodiment, the osteoporosis is idiopathic osteoporosis. In anotherembodiment, the osteoporosis is senile osteoporosis.

In another embodiment, the primary osteoporosis is Type I primaryosteoporosis. In another embodiment, the primary osteoporosis is Type IIprimary osteoporosis. Each type of osteoporosis represents a separateembodiment of the present invention.

According to this aspect of the invention and in one embodiment, thebone-related disorder is treated with a compound as herein described, ora combination thereof. In another embodiment, other bone-stimulatingcompounds can be provided to the subject, prior to, concurrent with orfollowing administration of a compound or compounds as herein described.In one embodiment, such a bone stimulating compound may comprise naturalor synthetic materials.

In one embodiment, the bone stimulating compound may comprise a bonemorphogenetic protein (BMP), a growth factor, such as epidermal growthfactor (EGF), a fibroblast growth factor (FGF), a transforming growthfactor (TGF, an insulin growth factor (IGF), a platelet-derived growthfactor (PDGF) hedgehog proteins such as sonic, indian and deserthedgehog, a hormone such as follicle stimulating hormone, parathyroidhormone, parathyroid hormone related peptide, activins, inhibins,follistatin, frizzled, frzb or frazzled proteins, BMP binding proteinssuch as chordin and fetuin, a cytokine such as IL-3, IL-7, GM-CSF, achemokine, such as eotaxin, a collagen, osteocalcin, osteonectin andothers, as will be appreciated by one skilled in the art.

In another embodiment, the compositions for use in treating a bonedisorder of this invention may comprise a compound or compounds asherein described, an additional bone stimulating compound, or compounds,and osteogenic cells. In one embodiment, an osteogenic cell may be astem cell or progenitor cell, which may be induced to differentiate intoan osteoblast. In another embodiment, the cell may be an osteoblast. Inanother embodiment, nucleic acids which encode bone-stimulatingcompounds may be administered to the subject, which is to be consideredas part of this invention.

In one embodiment, the methods of the present invention compriseadministering the compound for treating osteoporosis. In anotherembodiment, the methods of this invention comprise administering acompound in combination with SERMs for treating osteoporosis. In anotherembodiment, the SERMs are tamoxifene, 4-hydroxytamoxifene, idoxifene,toremifene, ospemifene, droloxifene, raloxifene, arzoxifene,bazedoxifene, PPT (1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole),DPN (diarylpropionitrile), lasofoxifene, pipendoxifene, EM-800, EM-652,nafoxidine, zindoxifene, tesmilifene, miproxifene phosphate, RU 58,688,EM 139, ICI 164,384, ICI 182,780, clomiphene, MER-25, diethylstibestrol,coumestrol, genistein, GW5638, LY353581, zuclomiphene, enclomiphene,delmadinone acetate, DPPE,(N,N-diethyl-2-{4-(phenylmethyl)-phenoxy}ethanamine), TSE-424, WAY-070,WAY-292, WAY-818, cyclocommunol, prinaberel, ERB-041, WAY-397, WAY-244,ERB-196, WAY-169122, MF-101, ERb-002, ERB-037, ERB-017, BE-1060, BE-380,BE-381, WAY-358, [18F]FEDNP, LSN-500307, AA-102, Ban zhi lian, CT-101,CT-102, or VG-101.

In another embodiment, the methods of the present invention compriseadministering the SARM compound, in combination with bisphosphonatessuch as alendronate, tiludroate, clodroniate, pamidronate, etidronate,alendronate, zolendronate, cimadronate, neridronate, minodronic acid,ibandronate, risedronate, or homoresidronate for treating osteoporosis.

In another embodiment, the methods of the present invention compriseadministering the compound, in combination with calcitonin such assalmon, Elcatonin, SUN-8577 or TJN-135 for treating osteoporosis.

In another embodiment, the methods of treating osteoporosis of thepresent invention comprise administering the SARM compound, incombination with a) vitamin D or derivative such as ZK-156979; b)vitamin D receptor ligand and analogues such as calcitriol, topitriol,ZK-150123, TEI-9647, BXL-628, Ro-26-9228, BAL-2299, Ro-65-2299 orDP-035; c) estrogen, estrogen derivative, or conjugated estrogens; d)antiestrogen, progestins, or synthetic estrogen/progestins; e) RANKligand mAb such as denosumab formerly AMG162 (Amgen); f) αvβ3 Integrinreceptor antagonist; g) osteoclast vacuolar ATPase inhibitor; h)antagonist of VEGF binding to osteoclast receptors; i) calcium receptorantagonist; j) PTh (parathyroid hormone) and analogues, PTHrP analogues(parathyroid hormone-related peptide); k) cathepsin K inhibitors(AAE581, etc.); 1) strontium ranelate; m) tibolone; n) HCT-1026,PSK3471; o) gallium maltolate; p) Nutropin AQ; q) prostaglandins (forosteo); r) p38 protein kinase inhibitor; s) bone morphogenetic protein;t) inhibitor of BMP antagonism; u) HMG-CoA reductase inhibitor; v)vitamin K or derivative; w) ipriflavone; x) fluoride salts; y) dietarycalcium supplement, and z) osteoprotegerin.

In one embodiment, the methods of this invention are useful in treatingdiseases or disorders caused by, or associated with a hormonal disorder,disruption or imbalance. In one embodiment, the hormonal disorder,disruption or imbalance comprises an excess of a hormone. In anotherembodiment, the hormonal disorder, disruption or imbalance comprises adeficiency of a hormone. In one embodiment, the hormone is a steroidhormone. In another embodiment, the hormone is an estrogen. In anotherembodiment, the hormone is an androgen. In another embodiment, thehormone is a glucocorticoid. In another embodiment, the hormone is acortico-steroid. In another embodiment, the hormone is luteinizinghormone (LH). In another embodiment, the hormone is follicle stimulatinghormone (FSH). In another embodiment, the hormone is any other hormoneknown in the art. In another embodiment, the hormonal disorder,disruption or imbalance is associated with menopause. In anotherembodiment, the hormonal disorder, disruption or imbalance is associatedwith andropause, andropausal vasomotor symptoms, andropausalgynecomastia, decreased muscle strength and/or function, decreased bonestrength and/or function and anger. In another embodiment, hormonedeficiency is a result of specific manipulation, as a byproduct oftreating a disease or disorder in the subject. For example, the hormonedeficiency may be a result of androgen depletion in a subject, as atherapy for prostate cancer in the subject. Each possibility representsa separate embodiment of the present invention.

In another embodiment the invention is directed to treating sarcopeniaor cachexia, and associated conditions related thereto, for examplediseases or disorders of the bone.

In one embodiment, this invention provides for the use of a compound asherein described, or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, for 1) treating a muscle wasting disorder; 2) preventing amuscle wasting disorder; 3) treating, preventing, suppressing,inhibiting or reducing muscle loss due to a muscle wasting disorder; 4)treating, preventing, inhibiting, reducing or suppressing muscle wastingdue to a muscle wasting disorder; and/or 5) treating, preventing,inhibiting, reducing or suppressing muscle protein catabolism due to amuscle wasting disorder; and/or treating, preventing, inhibiting,reducing or suppressing muscle wasting due to end stage renal disease orCKD; and/or 6) treating, preventing, inhibiting, reducing or suppressingfrailty.

In another embodiment, the use of a compound for treating a subjecthaving a muscle wasting disorder, or any of the disorders describedherein, includes administering a pharmaceutical composition including acompound as herein described. In another embodiment, the administeringstep includes intravenously, intraarterially, or intramuscularlyinjecting to said subject said pharmaceutical composition in liquidform; subcutaneously implanting in said subject a pellet containing saidpharmaceutical composition; orally administering to said subject saidpharmaceutical composition in a liquid or solid form; or topicallyapplying to the skin surface of said subject said pharmaceuticalcomposition.

A muscle is a tissue of the body that primarily functions as a source ofpower. There are three types of muscles in the body: a) skeletalmuscle—the muscle responsible for moving extremities and external areasof the bodies; b) cardiac muscle—the heart muscle; and c) smoothmuscle—the muscle that is in the walls of arteries and bowel.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or aninfection, or it can be due to a physiologic or metabolic state, such asdisuse deconditioning that can occur, for example, due to prolonged bedrest or when a limb is immobilized, such as in a cast. A wastingcondition can also be age associated. The loss of body mass that occursduring a wasting condition can be characterized by a loss of total bodyweight, or a loss of organ weight such as a loss of bone or muscle massdue to a decrease in tissue protein.

In one embodiment, “muscle wasting” or “muscular wasting”, used hereininterchangeably, refer to the progressive loss of muscle mass and/or tothe progressive weakening and degeneration of muscles, including theskeletal or voluntary muscles which control movement, cardiac muscleswhich control the heart, and smooth muscles. In one embodiment, themuscle wasting condition or disorder is a chronic muscle wastingcondition or disorder. “Chronic muscle wasting” is defined herein as thechronic (i.e. persisting over a long period of time) progressive loss ofmuscle mass and/or to the chronic progressive weakening and degenerationof muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of a pathology, disease, conditionor disorder. In one embodiment, the pathology, illness, disease orcondition is chronic. In another embodiment, the pathology, illness,disease or condition is genetic. In another embodiment, the pathology,illness, disease or condition is neurological. In another embodiment,the pathology, illness, disease or condition is infectious. As describedherein, the pathologies, diseases, conditions or disorders for which thecompounds and compositions of the present invention are administered arethose that directly or indirectly produce a wasting (i.e. loss) ofmuscle mass, that is a muscle wasting disorder.

In one embodiment, muscle wasting in a subject is a result of thesubject having a muscular dystrophie; muscle atrophy; X-linkedspinal-bulbar muscular atrophy (SBMA).

The muscular dystrophies are genetic diseases characterized byprogressive weakness and degeneration of the skeletal or voluntarymuscles that control movement. The muscles of the heart and some otherinvoluntary muscles are also affected in some forms of musculardystrophy. The major forms of muscular dystrophy (MD) are: duchennemuscular dystrophy, myotonic dystrophy, duchenne muscular dystrophy,becker muscular dystrophy, limb-girdle muscular dystrophy,facioscapulhumeral muscular dystrophy, congenital muscular dystrophy,oculopharyngeal muscular dystrophy, distal muscular dystrophy andemery-dreifuss muscular dystrophy.

Muscular dystrophy can affect people of all ages. Although some formsfirst become apparent in infancy or childhood, others may not appearuntil middle age or later. Duchenne MD is the most common form,typically affecting children. Myotonic dystrophy is the most common ofthese diseases in adults.

Muscle atrophy (MA) is characterized by wasting away or diminution ofmuscle and a decrease in muscle mass. For example, Post-Polio MA is amuscle wasting that occurs as part of the post-polio syndrome (PPS). Theatrophy includes weakness, muscle fatigue, and pain.

Another type of MA is X-linked spinal-bulbar muscular atrophy (SBMA—alsoknown as Kennedy's Disease). This disease arises from a defect in theandrogen receptor gene on the X chromosome, affects only males, and itsonset is in adulthood. Because the primary disease cause is an androgenreceptor mutation, androgen replacement is not a current therapeuticstrategy. There are some investigational studies where exogenoustestosterone propionate is being given to boost the levels of androgenwith hopes of overcoming androgen insensitivity and perhaps provide ananabolic effect. Still, use of supraphysiological levels of testosteronefor supplementation will have limitations and other potentially seriouscomplications.

Sarcopenia is a debilitating disease that afflicts the elderly andchronically ill patients and is characterized by loss of muscle mass andfunction. Further, increased lean body mass is associated with decreasedmorbidity and mortality for certain muscle-wasting disorders. Inaddition, other circumstances and conditions are linked to, and cancause muscle wasting disorders. For example, studies have shown that insevere cases of chronic lower back pain, there is paraspinal musclewasting.

Muscle wasting and other tissue wasting is also associated with advancedage. It is believed that general weakness in old age is due to musclewasting. As the body ages, an increasing proportion of skeletal muscleis replaced by fibrous tissue. The result is a significant reduction inmuscle power, performance and endurance.

Long term hospitalization due to illness or injury, or disusedeconditioning that occurs, for example, when a limb is immobilized, canalso lead to muscle wasting, or wasting of other tissue. Studies haveshown that in patients suffering injuries, chronic illnesses, burns,trauma or cancer, who are hospitalized for long periods of time, thereis a long-lasting unilateral muscle wasting, and a decrease in bodymass.

Injuries or damage to the central nervous system (CNS) are alsoassociated with muscle wasting and other wasting disorders. Injuries ordamage to the CNS can be, for example, caused by diseases, trauma orchemicals. Examples are central nerve injury or damage, peripheral nerveinjury or damage and spinal cord injury or damage. In one embodiment CNSdamage or injury comprise Alzheimer's diseases (AD); anger (mood);anorexia, anorexia nervosa, anorexia associated with aging and/orassertiveness (mood).

In another embodiment, muscle wasting or other tissue wasting may be aresult of alcoholism, and may be treated with the compounds andcompositions of the invention, representing embodiments thereof.

In one embodiment, the invention provides a use of a compound asdescribed herein or its analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof, for thetreatment of a wasting disease, disorder or condition in a subject.

In one embodiment, the wasting disease, disorder or condition beingtreated is associated with chronic illness

This invention is directed to treating, in some embodiments, any wastingdisorder, which may be reflected in muscle wasting, weight loss,malnutrition, starvation, or any wasting or loss of functioning due to aloss of tissue mass.

In some embodiments, wasting diseases or disorders, such as cachexia;malnutrition, tuberculosis, leprosy, diabetes, renal disease, chronicobstructive pulmonary disease (COPD), cancer, end stage renal failure,sarcopenia, emphysema, osteomalacia, or cardiomyopathy, may be treatedby the methods of this invention, via the administration of a SARMcompound as herein described, compositions comprising the same, with orwithout additional drugs, compounds, or agents, which provide atherapeutic effect for the condition being treated.

In some embodiments, wasting is due to infection with enterovirus,Epstein-Barr virus, herpes zoster, HIV, trypanosomes, influenze,coxsackie, rickettsia, trichinella, schistosoma or mycobacteria, andthis invention, in some embodiments, provides methods of treatmentthereof.

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Cardiac cachexia, i.e. a muscle protein wastingof both the cardiac and skeletal muscle, is a characteristic ofcongestive heart failure. Cancer cachexia is a syndrome that occurs inpatients with solid tumors and hematological malignancies and ismanifested by weight loss with massive depletion of both adipose tissueand lean muscle mass.

Cachexia is also seen in acquired immunodeficiency syndrome (AIDS),human immunodeficiency virus (HIV)-associated myopathy and/or muscleweakness/wasting is a relatively common clinical manifestation of AIDS.Individuals with HIV-associated myopathy or muscle weakness or wastingtypically experience significant weight loss, generalized or proximalmuscle weakness, tenderness, and muscle atrophy.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an infection ina subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound and an immunomodulatingagent, an anti-infective agent, a gene therapy agent, or a combinationthereof. In one embodiment, the anti-infective agent can be anantifungal, an antibacterial, an antiviral, or an antiparasitic agent,or a combination thereof. In some embodiments, infections compriseactinomycosis, anaplasmosis, anthrax, aspergillosis, bacteremia,bacterial mycoses, bartonella infections, botulism, brucellosis,burkholderia infections, campylobacter infections, candidiasis,cat-scratch disease, chlamydia infections, cholera, clostridiuminfections, coccidioidomycosis, cross infection, cryptococcosis,dermatomycoses, diphtheria, ehrlichiosis, Escherichia coli infections,fasciitis, necrotizing, Fusobacterium infections, gas gangrene,gram-negative bacterial infections, gram-positive bacterial infections,histoplasmosis, impetigo, Klebsiella infections, legionellosis, leprosy,leptospirosis, Listeria infections, lyme disease, maduromycosis,melioidosis, mycobacterium infections, mycoplasma infections, mycoses,nocardia infections, onychomycosis, plague, pneumococcal infections,pseudomonas infections, psittacosis, q fever, rat-bite fever, relapsingfever, rheumatic fever, Rickettsia infections, rocky mountain spottedfever, salmonella infections, scarlet fever, scrub typhus, sepsis,sexually transmitted diseases, Staphylococcal infections, Streptococcalinfections, tetanus, tick-borne diseases, tuberculosis, tularemia,typhoid fever, typhus, louse-borne, vibrio infections, yaws, yersiniainfections, zoonoses, zygomycosis, acquired immunodeficiency syndrome,adenoviridae infections, alphavirus infections, arbovirus infections,borna disease, bunyaviridae infections, caliciviridae infections,chickenpox, coronaviridae infections, coxsackievirus infections,cytomegalovirus infections, dengue, DNA virus infections, eethyma,contagious, encephalitis, arbovirus, Epstein-barr virus infections,erythema infectiosum, hantavirus infections, hemorrhagic fevers, viralhepatitis, viral human herpes simplex, herpes zoster, herpes zosteroticus, herpesviridae infections, infectious mononucleosis, human-lassafever, measles, molluscum, contagiosum, mumps, paramyxoviridaeinfections, phlebotomus fever, polyomavirus infections, rabies,respiratory syncytial virus infections, rift valley fever, RNA virusinfections, rubella, slow virus diseases, smallpox, subacute sclerosingpanencephalitis, tumor virus infections, warts, west nile fever, virusdiseases, yellow fever, amebiasis, anisakiasis, ascariasis, babesiosis,blastocystis hominis infections, bug bite, cestode infections, chagasdisease, cryptosporidiosis, cyclosporiasis, cysticercosis,dientamoebiasis, diphyllobothriasis, dracunculiasis, echinococcosis,ectoparasitic infestations, filariasis, giardiasis, helminthiasis,hookworm infections, larva migrans, leishmaniasis, lice infestations,loiasis, malaria, mite infestations, myiasis, onchocerciasis, protozoaninfections, scabies, schistosomiasis, (parasitic) skin diseases,strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis,trichomonas infections, trypanosomiasis, trypanosomiasis, african, orwhipworm infections.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with amusculoskeletal disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an antidiabeticagent, an agent treating the central nervous system, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, musculoskeletal diseasescomprise achondroplasia, acquired hyperostosis syndrome,acrocephalosyndactylia, arthritis, arthrogryposis, arthropathy,neurogenic bursitis, cartilage diseases, cleidocranial dysplasia,clubfoot, compartment syndromes, craniofacial dysostosis,craniosynostoses, dermatomyositis, Dupuytren's contracture, dwarfism,Ellis Van Creveld syndrome, enchondromatosis, eosinophilia-myalgiasyndrome, exostoses, fasciitis, fatigue syndrome, fibromyalgia, fibrousdysplasia of bone, fibrous dysplasia, polyostotic, flatfoot, footdeformities, Freiberg's disease, funnel chest, Goldenhar syndrome, gout,hallux valgus, hip dislocation, hyperostosis, intervertebral diskdisplacement, kabuki make-up syndrome, Klippel-Feil syndrome,Langer-Giedion syndrome, Legg-Perthes disease, lordosis, mandibulofacialdysostosis, melorheostosis, mitochondrial myopathies, muscle cramp,muscle spasticity, muscular dystrophies, musculoskeletal abnormalities,musculoskeletal diseases, myositis, myositis ossificans, myotubularmyopathy, osteitis deformans, osteoarthritis, osteochondritis,osteogenesis imperfecta, osteomyelitis, osteonecrosis, osteopetrosis,osteoporosis, poland syndrome, polychondritis, relapsing, polymyalgiarheumatica, polymyositis, rhabdomyolysis, rheumatic diseases, Russellsilver syndrome, Scheuermann's disease, scoliosis, Sever'sdisease/calceneal apophysitis, spinal diseases, spinal osteophytosis,spinal stenosis, spondylitis, ankylosing, spondylolisthesis, sprengel'sdeformity, synovitis, tendinopathy, tennis elbow, tenosynovitis,thanatophoric dysplasia, or Tietze's syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a digestivesystem disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the central nervous system, an agent treating thegastrointestinal system, an anti-infective agent, an agent treating ametabolic disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,gastrointestinal diseases comprise adenomatous polyposis coli, Alagillesyndrome, anus diseases, appendicitis, barrett esophagus, biliaryatresia, biliary tract diseases, Caroli disease, celiac disease,cholangitis, cholecystitis, cholelithiasis, colitis, ulcerative, Crohn'sdisease, deglutition disorders, duodenal ulcer, dysentery,enterocolitis, pseudomembranous, esophageal achalasia, esophagealatresia, esophagitis, exocrine pancreatic insufficiency, fatty liver,fecal incontinence, gastritis, gastritis, hypertrophic, gastroenteritis,gastroesophageal reflux, gastroparesis, hemorrhoids, hepatic veinthrombosis, hepatitis, hepatitis, chronic, hernia, diaphragmatic,hernia, hiatal, Hirschsprung disease, hypertension (HTN), portal HTN,inflammatory bowel diseases, intestinal diseases, intestinal neoplasms,intestinal neuronal dysplasia, intestinal obstruction, irritable bowelsyndrome, lactose intolerance, liver cirrhosis, liver diseases, meckeldiverticulum, pancreatic diseases, pancreatic neoplasms, pancreatitis,peptic ulcer, Peutz-Jeghers syndrome, proctitis, rectal diseases, rectalprolapse, short bowel syndrome, tracheoesophageal fistula, whippledisease, or Zollinger-Ellison syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a stomatognathicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an anti-infective agent,an agent treating a wasting disease, a gene therapy agent, an agenttreating the endocrine system, vitamins, or a combination thereof. Insome embodiments, stomatognathic diseases comprise ankyloglossia,bruxism, burning mouth syndrome, cheilitis, cherubism, cleft lip,dentigerous cyst, gingivitis, glossitis, benign migratory, herpeslabialis, Ludwig's angina, macroglossia, Melkersson-Rosenthal syndrome,periodontal diseases, Pierre Robin syndrome, prognathism, salivary glanddiseases, sialorrhea, stomatitis, aphthous, temporomandibular jointdisorders, temporomandibular joint dysfunction syndrome, or xerostomia.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a respiratorytract disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecentral nervous system, an agent treating the cardiovascular system, ananti-infective agent, an agent treating a wasting disease, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, respiratory tract diseasescomprise airway obstruction, apnea, asbestosis, asthma, asthma-inducedmuscle weakness or bone weakness, atelectasis, berylliosis, bronchialdiseases, bronchiectasis, bronchiolitis, bronchiolitis obliteransorganizing pneumonia, bronchitis, bronchopulmonary dysplasia, chronicobstructive pulmonary disease (COPD), common cold, cough, empyema,pleural, epiglottitis, glucocorticoid (GC)-induced myopathy orosteopenia hemoptysis, hypertension, pulmonary, hyperventilation,kartagener syndrome, lung abscess, lung diseases, meconium aspirationsyndrome, pleural effusion, pleurisy, pneumonia, pneumothorax, pulmonaryalveolar proteinosis, pulmonary disease, chronic obstructive, pulmonaryedema, pulmonary embolism, pulmonary emphysema, pulmonary fibrosis,respiratory distress syndrome, newborn-respiratory hypersensitivity,respiratory tract infections, rhinoscleroma, scimitar syndrome, severeacute respiratory syndrome, silicosis, sleep apnea, central stridor,tracheal stenosis, decreased muscle mass or bone mass due to asthma,wasting in chronic obstructive pulmonary disease (COPD), Wegener'sgranulomatosis, or whooping cough.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with anotorhinolaryngologic disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an anti-infectiveagent, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, otorhinolaryngologic diseases comprisecholesteatoma, middle ear, croup, deafness, epistaxis, hearing loss,hyperacusis, labyrinthitis, laryngitis, laryngomalacia, laryngostenosis,mastoiditis, Meniere's disease, nasal obstruction, nasal polyps, otitis,otorhinolaryngologic diseases, otosclerosis, pharyngitis, presbycusis,retropharyngeal abscess, rhinitis, sinusitis, tinnitus, tonsillitis,tympanic membrane perforation, vestibular neuronitis, vocal cordparalysis, or voice disorders.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a nervous systemdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecentral nervous system, an anti-infective agent, an agent treating ametabolic disease, an agent treating a wasting disease, a gene therapyagent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, nervous system diseasescomprise autonomic nervous system diseases, central nervous systemdiseases, cranial nerve diseases, demyelinating diseases, nervous systemmalformations, neurologic manifestations, or neuromuscular diseases.

In some embodiments, autonomic nervous system diseases comprisecausalgia, or reflex sympathetic dystrophy.

In some embodiments, central nervous system diseases compriseAlzheimer's disease, arachnoiditis, brain abscess, brain ischemia,central nervous system infections, cerebral palsy, cerebrovasculardisorders, corticobasal ganglionic degeneration (CBGD),Creutzfeldt-Jakob syndrome, Dandy-Walker syndrome, dementia,encephalitis, encephalomyelitis, epilepsy, epilepsy induced hypogonadaland/or hypermetabolic state, essential tremor, Friedreich ataxia,Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz syndrome,Huntington disease, hydrocephalus, hypoxia, insomnia, ischemic attack,kuru, Landau-Kleffner syndrome, Lewy Body disease, Machado-Josephdisease, meige syndrome, meningitis, bacterial meningitis, viral,migraine disorders, movement disorders, multiple system atrophy,myelitis, olivopontocerebellar atrophies, Parkinson's disease,parkinsonian disorders, poliomyelitis, postpoliomyelitis syndrome, priondiseases, pseudotumor cerebri, Shy-Drager syndrome, spasms, infantile,spinal cord diseases, supranuclear palsy, syringomyelia, thalamicdiseases, tic disorders, tourette syndrome, or uveomeningoencephaliticsyndrome. In some embodiments, the central nervous system disease iscystic fibrosis induced hypogonadal state.

In some embodiments, cranial nerve diseases comprise bell palsy, cranialnerve diseases, facial hemiatrophy, facial neuralgia, glossopharyngealnerve diseases, Moebius syndrome, or trigeminal neuralgia.

In some embodiments, central nervous system diseases comprise injuriesor damage to the central nervous system (CNS). In some embodiments,injuries or damage to the CNS may be associated with muscle wastingdisorders. Injuries or damage to the CNS can be, for example, caused bydiseases, trauma or chemicals. Examples are central nerve injury ordamage, peripheral nerve injury or damage and spinal cord injury ordamage.

Studies involving patients with spinal cord injuries (SCI) have shownthat central neurotransmitters may be altered after SCI causinghypothalamus-pituitary-adrenal axis dysfunction, whose disruption led toa significant decrease in testosterone and other hormone levels. SCI orother acute illness or trauma characteristically includes heightenedcatabolism in conjunction with the lowered anabolic activity resultingin a condition that is prone to loss of lean body tissue, which is oftenaccompanied by disturbed nutrient utilization. The effects of the lossof lean body mass include the development of wounds and impaired healingmechanisms, further compounding the problem. Because of poor nutritionand protein catabolism combined with immobilization, patients withspinal cord injury are at high risk for bed sores.

In one embodiment, a wide variety of injuries of the CNS may be treatedby the methods of the present invention. CNS injury may refer, in oneembodiment, to a breakdown of the membrane of a nerve cell, or, inanother embodiment, to the inability of the nerve to produce andpropagate nerve impulses, or in another embodiment, to the death of thecell. An injury includes damage that directly or indirectly affects thenormal functioning of the CNS. The injury may be a structural, physical,or mechanical impairment and may be caused by physical impact, as in thecase of a crushing, compression, or stretching of nerve fibers.Alternatively, the cell membrane may be destroyed by or degraded by anillness, a chemical imbalance, or a physiological malfunction such asanoxia (e.g., stroke), aneurysm, or reperfusion. A CNS injury includes,for example and without limitation, damage to retinal ganglion cells, atraumatic brain injury, a stroke-related injury, a cerebralaneurism-related injury, a spinal cord injury, including monoplegia,diplegia, paraplegia, hemiplegia and quadriplegia, a neuroproliferativedisorder, or neuropathic pain syndrome.

With injury to the spinal cord of a mammal, connections between nervesin the spinal cord are broken. Such injuries block the flow of nerveimpulses for the nerve tracts affected by the injury, with a resultingimpairment to both sensory and motor function. Injuries to the spinalcord may arise from compression or other contusion of the spinal cord,or a crushing or severing of the spinal cord. A severing of the spinalcord, also referred to herein as a “transection,” may be a completesevering or, may be an incomplete severing of the spinal cord.

In some embodiments, the methods of treating a subject suffering form aCNS injury or, in other embodiments, spinal cord injury, may beaccompanied by treatment of the subject with electrical stimulation ofthe injured site and the administration of a purine nucleoside, oranalog thereof, for example as described in United States PatentApplication Publication Number 20040214790AI.

In some embodiments, demyelinating diseases compriseadrenoleukodystrophy, alexander disease, canavan disease, demyelinatingdisease, diffuse cerebral sclerosis of schilder, leukodystrophy-globoidcell, leukodystrophy-metachromatic, multiple sclerosis, or neuromyelitisoptica.

In some embodiments, nervous system malformations comprise Amold-Chiarimalformation, Charcot-Marie-Tooth disease, encephalocele, hereditarymotor and sensory neuropathies, septo-optic dysplasia, spina bifidaocculta, or spinal dysraphism.

In some embodiments, neurologic manifestations comprise agnosia,amnesia, anomia, aphasia, apraxias, back pain, Brown-Sequard syndrome,cerebellar ataxia, chorea, communication disorders, confusion,dizziness, dyslexia, dystonia, facial paralysis, fasciculation, gaitdisorders, neurologic-headache, hemiplegia, memory disorders, mentalretardation, mutism, myoclonus, neck pain, nonverbal learning disorder,olfaction disorders, pain, paralysis, phantom limb, prosopagnosia,quadriplegia, seizures, spasm, speech disorders, synesthesia tardivedyskinesia, taste disorders, torticollis, tremor, trismus,unconsciousness, or vertigo.

In some embodiments, neuromuscular diseases comprise amyotrophic lateralsclerosis, brachial plexus neuritis, brachial plexus neuropathies,bulbar palsy, carpal tunnel syndrome, cubital tunnel syndrome, diabeticneuropathies, dysautonomia, guillain-barre syndrome, hereditary sensoryand autonomic neuropathies, miller fisher syndrome, motor neurondisease, muscular atrophy, spinal, myasthenia gravis, myopathies,structural, congenital, nerve compression syndromes, neuralgia,neuromuscular diseases, paralyses, familial periodic, peripheral nervoussystem diseases, poems syndrome, polyneuropathies, polyradiculopathy,refsum disease, sciatica, spinal muscular atrophies of childhood,stiff-person syndrome, thoracic outlet syndrome, or ulnar nervecompression syndromes.

In one embodiment, methods of treating a subject with a nervous systemdisease encompass treating any secondary conditions in the subject,which arise due to the subject having a nervous system disease, some ofwhich are described herein.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an ophthalmicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound and ananti-cancer agent, an immunomodulating agent, an agent treating thecardiovascular system, an anti-infective agent, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodimentsophthalmic disease comprise acute zonal occult outer retinopathy, Adiesyndrome, albinism, ocular-amaurosis, fugax, amblyopia, aniridia,anisocoria, anopthalmos, aphakia, astigmatism, blepharitis,blepharoptosis, blepharospasm, blindness, cataract, chalazion,chorioretinitis, choroideremia, coloboma, color vision defects,conjunctivitis, corneal diseases, corneal dystrophies, corneal edema,corneal ulcer, diabetic retinopathy, diplopia, distichiasis, dry eyesyndromes, Duane retraction syndrome, ectropion, entropion, esotropia,exfoliation syndrome, exotropia, eye hemorrhage, eye neoplasms, eyeliddiseases, floaters, general fibrosis syndrome, glaucoma, gyrate atrophy,hemianopsia, Hermanski-Pudlak syndrome, hordeolum, Horner syndrome,hyperopia, hyphema, iritis, Kearns-Sayer syndrome, keratitis,keratoconus, lacrimal apparatus diseases, lacrimal duct obstruction,lens diseases, macular degeneration, micropthalmos, myopia, nystagmus,pathologic, ocular motility disorders, oculomotor nerve diseases,opthalmoplegia, optic atrophies, optic nerve diseases, optic neuritis,optic neuropathy, orbital cellulitis, papilledema, peter's anomaly,presbyopia, pterygium, pupil disorders, refractive errors, retinaldetachment, retinal diseases, retinal vein occlusion, retinitispigmentosa, retinopathy of prematurity, retinoschisis, scleritis,scotoma, strabismus, Thygeson's superficial punctate keratitis,trachoma, uveitis, white dot syndrome, vision disorders, or vitreousdisorders

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an urologicand/or male genital disease in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundand an anti-cancer agent, an immunomodulating agent, an antidiabeticagent, an agent treating the gastrointestinal system, an anti-infectiveagent, an agent treating the kidney, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, an urologic and/or male genital diseases compriseanti-glomerular basement membrane disease, balanitis, bladder exstrophy,bladder neoplasms, cryptorchidism, cystitis, interstitial, diabetesinsipidus, nephrogeni.c, epididymitis, fournier gangrene,glomerulonephritis, Goodpasture syndrome, hematospermia, hematuria,hemolytic-uremic syndrome, hydronephrosis, hypospadias, impotence,infertility, kidney calculi, kidney failure, acute, kidney failure,chronic, kidney tubular necrosis, acute, medullary sponge kidney,multicystic dysplastic kidney, nephritis, hereditary, nephrosis,nephrotic syndrome, nocturia, oliguria, penile diseases, penileinduration, penile neoplasms, phimosis, priapism, prostatic diseases,benign prostate hyperplasia, prostatic neoplasms, proteinuria,pyelonephritis, Reiter disease, renal artery obstruction, spermatic cordtorsion, testicular diseases, urethral stricture, urethritis, urinaryretention, urinary tract infections, urination disorders, urologic andmale genital diseases, urologic diseases, varicocele, yesico, orurethral reflux.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a dermatologicaldisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound andanti-cancer agent, an immunomodulating agent, an agent treating adermatological disorder, an anti-infective agent, a gene therapy agent,an agent treating the endocrine system, vitamins, or a combinationthereof. In some embodiments, dermatological disorders comprise acne,actinic keratosis, alopecia, androgenic alopecia, alopecia greata,alopecia secondary to chemotherapy, alopecia secondary to radiationtherapy, alopecia induced by scarring, alopecia induced by stress,angioma, athlete's foot, aquagenic pruritus, atopic dermatitis,baldness, premature baldness, male pattern baldness, androgenicbaldness, basal cell carcinoma, burns, bed sore, Behcet's disease,blepharitis, boil, Bowen's disease, bullous pemphigoid, canker sore,carbuncles, cellulitis, chloracne, chronic dermatitis of the hands andfeet, dyshidrosis, cold sores, contact dermatitis, creeping eruption,dandruff, dermatitis, dermatitis herpetiformis, dermatofibroma, diaperrash, eczema, epidermolysis bullosa, erysipelas, erythroderma, frictionblister, genital wart, hidradenitis, suppurativa, hives, hyperhidrosis,ichthyosis, impetigo, jock itch, Kaposi's sarcoma, keloid,keratoacanthoma, keratosis pilaris, lice infection, lichen planus,lichen simplex chronicus, lipoma, lymphadenitis, malignant melanoma,melasma, miliaria, molluscum contagiosum, nummular dermatitis, paget'sdisease of the nipple, pediculosis, pemphigus, perioral dermatitis,photoallergy, photosensitivity, pityriasis rosea, pityriasis rubrapilaris, psoriasis, raynaud's disease, ring worm, rosacea, scabies,scleroderma, sebaceous cyst, seborrheic keratosis, seborrhoeicdermatitis, shingles, skin cancer, skin tags, spider veins, squamouscell carcinoma, stasis dermatitis, tick bite, tinea barbae, tineacapitis, tinea corporis, tinea cruris, tinea pedis, tinea unguium, tineaversicolor, tinea, tungiasis, vitiligo, or warts.

In one embodiment, the dermatological disorder is a wound or a burn. Insome embodiments, wounds and/or ulcers are found protruding from theskin or on a mucosal surface or as a result of an infarction in anorgan. A wound may be a result of a soft tissue defect or a lesion or ofan underlying condition. In one embodiment, the term “wound” denotes abodily injury with disruption of the normal integrity of tissuestructures. The term is also intended to encompass the terms “sore”,“lesion”, “necrosis” and “ulcer”. In one embodiment, the term “sore”refers to any lesion of the skin or mucous membranes and the term“ulcer” refers to a local defect, or excavation, of the surface of anorgan or tissue, which is produced by the sloughing of necrotic tissue.Lesion generally relates to any tissue defect. Necrosis is related todead tissue resulting from infection, injury, inflammation orinfarctions. All of these are encompassed by the term “wound”, whichdenotes any wound at any particular stage in the healing processincluding the stage before any healing has initiated or even before aspecific wound like a surgical incision is made (prophylactictreatment).

Examples of wounds which can be prevented and/or treated in accordancewith the present invention are, e.g., aseptic wounds, contused wounds,incised wounds, lacerated wounds, non-penetrating wounds (i.e. wounds inwhich there is no disruption of the skin but there is injury tounderlying structures), open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds, subcutaneous wounds, etc.Examples of sores are bed sores, canker sores, chrome sores, cold sores,pressure sores etc. Examples of ulcers are, e.g., peptic ulcer, duodenalulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemiculcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer,submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer,veneral ulcer, e.g. caused by gonorrhoea (including urethritis,endocervicitis and proctitis). Conditions related to wounds or soreswhich may be successfully treated according to the invention are burns,anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae,folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There isoften a certain overlap between the use of the terms “wound” and “ulcer”and “wound” and “sore” and, furthermore, the terms are often used atrandom. Therefore as mentioned above, in the present context the term“wounds” encompasses the term “ulcer”, “lesion”, “sore” and“infarction”, and the terms are indiscriminately used unless otherwiseindicated.

The kinds of wounds to be treated according to the invention includealso i) general wounds such as, e.g., surgical, traumatic, infectious,ischemic, thermal, chemical and bullous wounds; ii) wounds specific forthe oral cavity such as, e.g., post-extraction wounds, endodontic woundsespecially in connection with treatment of cysts and abscesses, ulcersand lesions of bacterial, viral or autoimmunological origin, mechanical,chemical, thermal, infectious and lichenoid wounds; herpes ulcers,stomatitis aphthosa, acute necrotising ulcerative gingivitis and burningmouth syndrome are specific examples; and iii) wounds on the skin suchas, e.g., neoplasm, burns (e.g. chemical, thermal), lesions (bacterial,viral, autoimmunological), bites and surgical incisions. Another way ofclassifying wounds is as i) small tissue loss due to surgical incisions,minor abrasions and minor bites, or as ii) significant tissue loss. Thelatter group includes ischemic ulcers, pressure sores, fistulae,lacerations, severe bites, thermal burns and donor site wounds (in softand hard tissues) and infarctions.

In other aspects of the invention, the wound to be prevented and/ortreated is selected from the group consisting of aseptic wounds,infarctions, contused wounds, incised wounds, lacerated wounds,non-penetrating wounds, open wounds, penetrating wounds, perforatingwounds, puncture wounds, septic wounds and subcutaneous wounds.

Other wounds which are of importance in connection with the presentinvention are wounds like ischemic ulcers, pressure sores, fistulae,severe bites, thermal burns and donor site wounds.

In one embodiment, the compound as described herein is useful in woundhealing as an adjunct to physical therapy/rehabilitation, or as ananabolic agent. In another embodiment, the compound as described hereinis useful in promoting healing of anterior cruciate ligament (ACL) ormedial cruciate ligament (MCL) injuries, or accelerating recovery afterACL or MCL surgery. In another embodiment, the compound as describedherein is useful in enhancing athletic performance. In anotherembodiment, the compound as described herein is useful in treatingburns. In another embodiment, the compound as described herein is usefulin stimulating cartilage regrowth. In another embodiment, the compoundas described herein is useful in preventing, treating, or reversing ofcatabolism associated with prolonged critical illness, pulmonarydysfunction, ventilator dependency, aging, AIDS, trauma, surgery,congestive heart failure, cardiac myopathy, burns, cancer, COPD. Inanother embodiment, the compound as described herein is useful inpreventing or reversing protein catabolism due to trauma. In anotherembodiment, the compound as described herein is useful as a) adjunct tocauterization therapy (laser or radio) as is used in surgery to promotewound healing, b) adjunct to cryotherapy to promote wound healing, c)adjunct to chemotherapy to prevent side effects such as alopecia,hypogonadism, muscle wasting, osteopenia, osteoporosis, sarcopenia,increased LDL, triglyceride (TG) or total cholesterol, decreased HDL. Inanother embodiment, the compound as described herein is useful inchronic catabolic state (coma, wasting conditions, starvation, eatingdisorders); concomitant bone fracture and muscle damage; criticalillness in which muscle or bone wasting are apparent; and/or connectivetissue diseases and disorders.

Ischemic ulcers and pressure sores are wounds, which normally only healvery slowly and especially in such cases an improved and more rapidhealing is of course of great importance for the patient. Furthermore,the costs involved in the treatment of patients suffering from suchwounds are markedly reduced when the healing is improved and takes placemore rapidly.

Donor site wounds are wounds which e.g. occur in connection with removalof hard tissue from one part of the body to another part of the bodye.g. in connection with transplantation. The wounds resulting from suchoperations are very painful and an improved healing is therefore mostvaluable.

The term “skin” is used in a very broad sense embracing the epidermallayer of the skin and in those cases where the skin surface is more orless injured also the dermal layer of the skin. Apart from the stratumcorneum, the epidermal layer of the skin is the outer (epithelial) layerand the deeper connective tissue layer of the skin is called the dermis.

In some embodiments, burns are associated with reduced testosteronelevels, and hypogonadism is associated with delayed wound healing. Inone embodiment, the methods of this invention, provide for treating asubject suffering from a wound or a burn.

In some embodiments, the present invention provides a method forpromoting healing of anterior cruciate ligament (ACL) or medial cruciateligament (MCL) injuries, or accelerating recovery after ACL or MCLsurgery.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with an endocrinedisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound andanti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating a dermatological disorder, anagent treating the central nervous system, an anti-infective agent, anagent treating the liver, an agent treating the kidney, an agenttreating a metabolic disease, an agent treating a wasting disease, agene therapy agent, an agent treating the endocrine system, vitamins, ora combination thereof. In some embodiments, endocrine disorders compriseacromegaly, Addison disease, adrenal gland diseases, adrenalhyperplasia, congenital, androgen-insensitivity syndrome, congenitalhypothyroidism, Cushing syndrome, diabetes insipidus, diabetes mellitus,diabetes mellitus-type 1, diabetes mellitus-type 2, diabetic,ketoacidosis, empty Sella syndrome, endocrine gland neoplasms, endocrinesystem diseases, gigantism, gonadal disorders, graves disease,hermaphroditism, hyperaldosteronism, hyperglycemic hyperosmolarnonketotic coma, hyperpituitarism, hyperprolactinemia, hyperthyroidism,hypogonadism, hypopituitarism, hypothyroidism, Kallmann syndrome, Nelsonsyndrome, parathyroid diseases, pituitary diseases,polyendocrinopathies, autoimmune, puberty, delayed, puberty, precocious,renal osteodystrophy, thyroid diseases, thyroid hormone resistancesyndrome, thyroid neoplasms, thyroid nodule, thyroiditis, thyroiditis,autoimmune, thyroiditis, subacute, or Wolfram syndrome.

In one embodiment, “Hypogonadism” is a condition resulting from orcharacterized by abnormally decreased functional activity of the gonads,with retardation of growth and sexual development.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with urogenitaldisease and/or fertility in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and anti-cancer agent, an immunomodulating agent, ananti-infective agent, an agent treating the kidney, gene therapy agent,an agent treating the endocrine system, vitamins, or a combinationthereof. In some embodiments, urogenital diseases and/or fertilitydiseases comprise abortion, spontaneous-adhesions-pelvic, candidiasis,vulvovaginal, depression-postpartum, diabetes, gestational, dyspareunia,dystocia, eclampsia, endometriosis, fetal death, fetal growthretardation, premature rupture of fetal membranes, female genitaldiseases, female genital neoplasms, hydatidiform mole, hyperemesisgravidarum, infertility, ovarian cysts, ovarian torsion, pelvicinflammatory disease, placenta diseases, placental insufficiency,polycystic ovary syndrome, polyhydramnios, postpartum hemorrhage,pregnancy complications, pregnancy, ectopic, pruritus vulvae, puerperaldisorders, puerperal infection, salpingitis, trophoblastic neoplasms,uterine cervix incompetence, uterine inversion, uterine prolapse,vaginal diseases, vulvar diseases, vulvar lichen sclerosis.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with hemic and/orlymphatic disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, ananti-infective agent, an agent treating the liver, an agent treating thekidney, an agent treating a metabolic disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, hemic and/or lymphatic diseases compriseafibrinogenemia, anemia, aplastic anemia, hemolytic anemia, congenitalnonspherocytic anemia, megaloblastic anemia, pernicious anemia, sicklecell anemia, renal anemia, angiolymphoid hyperplasia with eosinophilia,antithrombin III deficiency, Bernard-Soulier syndrome, blood coagulationdisorders, blood platelet disorders, blue rubber bleb nevus syndrome,Chediak-Higashi syndrome, cryoglobulinemia, disseminated intravascularcoagulation, eosinophilia, Erdheim-Chester disease, erythroblastosis,fetal, evans syndrome, factor V deficiency, factor VII deficiency,factor X deficiency, factor XI deficiency, factor XII deficiency,fanconi anemia, giant lymph node hyperplasia, hematologic diseases,hemoglobinopathies, hemoglobinuria, paroxysmal, hemophilia a, hemophiliab, hemorrhagic disease of newborn, histiocytosis, histiocytosis,langerhans-cell, histiocytosis, non-langerhans-cell, job's syndrome,leukopenia, lymphadenitis, lymphangioleiomyomatosis, lymphedema,methemoglobinemia, myelodysplastic syndromes, myelofibrosis, myeloidmetaplasia, myeloproliferative disorders, neutropenia, paraproteinemias,platelet storage pool deficiency, polycythemia vera, protein cdeficiency, protein s deficiency, purpura, thrombocytopenic, purpura,thrombotic thrombocytopenic, RH-isoimmunization, sarcoidosis,sarcoidosis, spherocytosis, splenic rupture, thalassemia,thrombasthenia, thrombocytopenia, Waldenstrom macroglobulinemia, or VonWillebrand disease.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a congenital,hereditary, or neonatal disease in a subject. In one embodiment, themethod comprises administering to a subject a composition comprising acompound of this invention and anti-cancer agent, an immunomodulatingagent, an antidiabetic agent, an agent treating the cardiovascularsystem, an agent treating the gastrointestinal system, an agent treatinga dermatological disorder, an agent treating the central nervous system,an anti-infective agent, an agent treating the liver, an agent treatingthe kidney, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,congenital, hereditary, and neonatal diseases comprise Aicardi syndrome,amniotic band syndrome, anencephaly, Angelman syndrome, ataxiatelangiectasia, Bannayan-Zonana syndrome, Barth syndrome, basal cellnevus syndrome, Beckwith-Wiedemann syndrome, bloom syndrome,branchio-oto-renal syndrome, cat eye syndrome, cerebral gigantism-chargesyndrome, chromosome 16 abnormalities, chromosome 18 abnormalities,chromosome 20 abnormalities, chromosome 22 abnormalities, Costellosyndrome, cri-du-chat syndrome, Currarino syndrome, cystic fibrosis,de-Lange syndrome, distal trisomy 10q, down syndrome, ectodermaldysplasia, fetal alcohol syndrome, fetal diseases, fetofetaltransfusion, fragile x syndrome, Freeman-Sheldon syndrome,gastroschisis, genetic diseases, inborn, hernia, umbilical,holoprosencephaly, incontinentia pigmenti, Ivemark syndrome, Jacobsensyndrome, jaundice, Klinefelter syndrome, Larsen syndrome, Laurence-moonsyndrome, lissencephaly, microcephaly, monosomy 9p, nail-patellasyndrome, neurofibromatoses, neuronal ceroid-lipofuscinosis, Noonansyndrome, ochoa syndrome (urofacial syndrome, hydronephrosis withpeculiar facial expression), oculocerebrorenal syndrome,Pallister-Killian syndrome, Prader-Willi syndrome, proteus syndrome,prune belly syndrome, Rett syndrome, Robinow syndrome, Rubinstein-Taybisyndrome, schizencephaly, situs inversus, Smith-Lemli-Opitz syndrome,Smith-Magenis syndrome, Sturge-Weber syndrome, syphilis, congenital,trichothiodystrophy, triple-x females, trisomy 13 (Patau syndrome),trisomy 9, turner syndrome, twins, conjoined, Usher syndrome,Waardenburg's syndrome, Werner syndrome, or Wolf-Hirschhom syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a connectivetissue disease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, an agenttreating a dermatological disorder, an anti-infective agent, an agenttreating a metabolic disease, an agent treating a wasting disease, agene therapy agent, an agent treating the endocrine system, vitamins, ora combination thereof. In some embodiments, connective tissue diseasescomprise ankylosing spondylitis, Ehlers-Danlos syndrome,Henoch-Schonlein purpura, Kawasaki disease, Marfan syndrome,polyarteritis nodosa, polymyositis, psoriatic arthritis, reactivearthritis, rheumatoid arthritis, scleroderma, Sjogren's syndrome,xerophthalmia, Still's disease, systemic lupus erythematosus, Takayasudisease, or Wegener's granulomatosis.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a metabolicdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and antidiabetic agent, an agent treating the gastrointestinalsystem, an agent treating a dermatological disorder, an agent treatingthe central nervous system, an anti-infective agent, an agent treatingthe liver, an agent treating the kidney, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.In some embodiments, metabolic diseases comprise acid-base imbalance,acidosis, alkalosis, alkaptonuria, alpha-mannosidosis, amino acidmetabolism inborn errors, amyloidosis, iron-deficiency anemia, ascorbicacid deficiency, avitaminosis, beriberi, biotinidase deficiency,carbohydrate-deficient glycoprotein syndrome, carnitine disorders,cystinosis, cystinuria, dehydration, fabry disease, fatty acid oxidationdisorders, fucosidosis, galactosemias, Gaucher disease, Gilbert disease,glucosephosphate dehydrogenase deficiency, glutaric acidemia, glycogenstorage disease, Hartnup disease, hemochromatosis, hemosiderosis,hepatolenticular degeneration, histidinemia, homocystinuria,hyperbilirubinemia, hypercalcemia, hyperinsulinism, hyperkalemia,hyperlipidemia, hyperoxaluria, hypervitaminosis A, hypocalcemia,hypoglycemia, hypokalemia, hyponatremia, hypophosphatasia, insulinresistance, iodine deficiency, iron overload, jaundice, chronicidiopathic, leigh disease, lesch-nyhan syndrome, leucine metabolismdisorders, lysosomal storage diseases, magnesium deficiency, maple syrupurine disease, Melas syndrome, Menkes kinky hair syndrome, metabolicdiseases, metabolic syndrome x, metabolism, inborn errors, mitochondrialdiseases, mucolipidoses, mucopolysaccharidoses, Niemann-Pick diseases,obesity, ornithine carbamoyltransferase deficiency disease,osteomalacia, pellagra, peroxisomal disorders, phenylketonurias,porphyria, erythropoietic, porphyrias, progeria, pseudo, gaucherdisease, refsum disease, Reye syndrome, rickets, Sandhoff disease,starvation, tangier disease, Tay-Sachs disease, tetrahydrobiopterindeficiency, trimethylaminuria, tyrosinemias, urea cycle disorders,water-electrolyte imbalance, Wernicke encephalopathy, vitamin Adeficiency, vitamin B12 deficiency, vitamin B deficiency, Wolmandisease, or Zellweger syndrome.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a disorder ofenvironmental origin in a subject. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating adermatological disorder, an agent treating the central nervous system,an anti-infective agent, an agent treating the liver, an agent treatingthe kidney, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments,disorders of environmental origin comprise barotrauma, bites and stings,brain concussion, burns, central cord syndrome, craniocerebral trauma,electric injuries, fractures, bone, frostbite, heat stress disorders,motion sickness, occupational diseases, poisoning, shaken baby syndrome,shoulder injuries, space motion sickness, spinal cord injuries, tickparalysis, or wounds (penetrating and non-penetrating).

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a behaviormechanism in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an agent treating the cardiovascular system, an agenttreating the central nervous system, a gene therapy agent, an agenttreating the endocrine system, vitamins, or a combination thereof. Insome embodiments, behavior mechanisms comprise aggression, attitude todeath, codependency, self-injurious behavior, sexual behavior, or socialbehavior.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a mentaldisorder in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and an agent treating the central nervous system, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, mental disorders compriseAsperger syndrome, attention deficit disorder with hyperactivity,autistic disorder, bipolar disorder, borderline personality disorder,capgras syndrome, child behavior disorders, combat disorders,cyclothymic disorder, dependent personality disorder, depressivedisorder, dissociative disorders, dysthymic disorder, eating disorders,firesetting behavior, hypochondriasis, impulse control disorders,Kleine-Levin syndrome, mental disorders, mental disorders diagnosed inchildhood, multiple personality disorder, Munchausen syndrome,Munchhausen syndrome, Munchhausen by proxy, narcissistic personalitydisorder, narcolepsy, obsessive-compulsive disorder, paraphilias, phobicdisorders, psychotic disorders, restless legs syndrome, schizophrenia,seasonal affective disorder, sexual and gender disorders, sexualdysfunctions, psychological, sleep disorders, somatoform disorders,stress disorders, post-traumatic, substance-related disorders, suicidalbehavior, or trichotillomania.

In one embodiment, “depression” refers to an illness that involves thebody, mood and thoughts that affects the way a person eats, sleeps andthe way one feels about oneself, and thinks about things. The signs andsymptoms of depression include loss of interest in activities, loss ofappetite or overeating, loss of emotional expression, an empty mood,feelings of hopelessness, pessimism, guilt or helplessness, socialwithdrawal, fatigue, sleep disturbances, trouble concentrating,remembering, or making decisions, restlessness, irritability, headaches,digestive disorders or chronic pain.

In one embodiment, “cognition” refers to the process of knowing,specifically the process of being aware, knowing, thinking, learning andjudging. Cognition is related to the fields of psychology, linguistics,computer science, neuroscience, mathematics, ethology and philosophy. Inone embodiment, “mood” refers to a temper or state of the mind. Ascontemplated herein, alterations mean any change for the positive ornegative, in cognition and/or mood.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a liver diseasein a subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention andanti-cancer agent, an immunomodulating agent, an agent treating thegastrointestinal system, an anti-infective agent, an agent treating theliver, an agent treating a metabolic disease, an agent treating awasting disease, a gene therapy agent, an agent treating the endocrinesystem, vitamins, or a combination thereof. In some embodiments, liverdiseases comprise liver cancer, primary biliary cirrhosis, autoimmunehepatitis, chronic liver disease, cirrhosis of the liver, hepatitis,viral hepatitis (hepatitis a, hepatitis b, chronic hepatitis b,hepatitis c, chronic hepatitis c, hepatitis d, hepatitis e, hepatitisx), liver failure, jaundice, neonatal jaundice, hepatoma, liver cancer,liver abscess, alcoholic liver disease, hemochromatosis, Wilson'sdisease, portal hypertension, primary sclerosing cholangitis,sarcoidosis, tapeworms, alveolar hydatid disease, fascioliasis,schistosomiasis, gaucher disease, Zellweger syndrome, alcoholism, foodpoisoning, pneumococcal pneumonia or vibrio vulnificus.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a kidney diseasein a subject. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention andanti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the gastrointestinal system, an anti-infective agent, anagent treating the kidney, an agent treating a metabolic disease, a genetherapy agent, an agent treating the endocrine system, vitamins, or acombination thereof. In some embodiments, kidney diseases compriseacromegaly, acute renal failure (ARF), amyloidosis, autosomal dominantpolycystic kidney disease, kidney stones, kidney cysts, autosomalrecessive polycystic kidney disease, chronic renal failure (CRF),chronic renal disease, coffin-Lowry syndrome, cor pulmonale,cryoglobulinemia, diabetic nephropathy, dyslipidemia, Gaucher disease,glomerulonephritis, goodpasture syndrome, hemolytic uremic syndrome,hepatitis, kidney cancer, kidney stones, leukemia, lipoproteinemia,lupus, multiple myeloma, nephritis, polyartekidney cysts, poststreptococcal glomerulonephritis, glomerulonephritis, kidney pain,preeclampsia, renal tuberculosis, pyelonephritis, renal tubular acidosiskidney disease, streptococcal toxic shock syndrome, thromboembolism,toxoplasmosis, urinary tract infections, vesicoureteral reflux, orwilliams syndrome.

In one embodiment, the kidney disease or disorder is acute, or inanother embodiment, chronic.

In one embodiment, clinical indications of a kidney disease or disorder,wherein the methods of treatment may be useful include urinary casts,measured GFR, or other markers of renal function.

In one embodiment, the methods of this invention are useful in subjectspredisposed to kidney diseases or disorders. In one embodiment, thephrase “predisposed to a kidney disease or disorder” with respect to asubject is synonymous with the phrase “subject at risk”, and includes asubject at risk of acute or chronic renal failure, or at risk of theneed for renal replacement therapy, if the subject is reasonablyexpected to suffer a progressive loss of renal function associated withprogressive loss of functioning nephron units. Whether a particularsubject is at risk is a determination which may routinely be made by oneof ordinary skill in the relevant medical or veterinary art.

In one embodiment, subjects with kidney disease, in particular malesubjects with end-stage renal disease (ESRD) suffer from hypogonadism,with some having concomitant moderate to severe protein-energymalnutrition (PEM), which leads to higher required doses oferythropoietin (EPO), lower quality of life (QOL) scores, and highermortality. Many have other symptoms associated with hypogonadism,including fatigue, lack of apetite, muscle weakness, etc. In someembodiments, the treatment methods of this invention are useful intreating symptoms associated with hypogonadism, brought about in thesubject by androgen deficiency in a female (ADIF); androgen deficiencyin aging male (ADAM) to include fatigue, depression, decreased libido,erectile dysfunction, decreased cognition, decreased mood; androgeninsufficiency (male or female), androgen deficiency (male or female).

In one embodiment, diabetic nephropathy is a complication of diabetesthat evolves early, typically before clinical diagnosis of diabetes ismade. The earliest clinical evidence of nephropathy is the appearance oflow but abnormal levels (>30 mg/day or 20 μg/min) of albumin in theurine (microalbuminuria), followed by albuminuria (>300 mg/24 h or 200μg/min) that develops over a period of 10-15 years. In patients withtype I diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls over acourse of times, which may be several years, resulting in End StageRenal Disease (ESRD) in diabetic individuals.

Hypertension is another comorbid factor for renal disease. In someembodiments, treatment of renal disease according to the presentinvention may comprise concomitant treatment with a compound of thisinvention and an agent which treats hypertension.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdisease in a subject. In one embodiment, the method comprisesadministering to a subject a composition comprising a compound of thisinvention and anti-cancer agent, an immunomodulating agent, anantidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, vitamins, or a combination thereof. In someembodiments, wasting diseases comprise muscle injury, bed rest,immobility, nerve injury, neuropathy, diabetic neuropathy, alcoholicneuropathy, subacute combined degeneration of the spinal cord, diabetes,rheumatoid arthritis, umotor neurone diseases, Duchenne musculardystrophy, carpal tunnel syndrome, chronic infection, tuberculosis,Addison's disease, adult sma, limb muscle atrophy, alcoholic neuropathy,anorexia, anorexia nervosa, anorexia associated with cachexia, anorexiaassociated with aging, back tumour, dermatomyositis, hip cancer,inclusion body myositis, incontinentia pigmenti, intercostal neuralgia,juvenile rheumatoid arthritis, Legg-Calve-Perthes disease, muscleatrophy, multifocal motor neuropathy, nephrotic syndrome, osteogenesisimperfecta, post-polio syndrome, rib tumor, spinal muscular atrophy,reflex sympathetic dystrophy syndrome, or Tay-Sachs.

A wasting condition or disorder is defined herein as a condition ordisorder that is characterized, at least in part, by an abnormal,progressive loss of body, organ or tissue mass. A wasting condition canoccur as a result of a pathology such as, for example, cancer, or it canbe due to a physiologic or metabolic state, such as disusedeconditioning that can occur, for example, due to prolonged bed rest orwhen a limb is immobilized, such as in a cast, or with the occurrence ofmultiple wounds, including, for example, amputation, as occurs indiabetics, and other conditions, as will be appreciated by one skilledin the art. A wasting condition can also be age associated. The loss ofbody mass that occurs during a wasting condition can be characterized bya loss of total body weight, or a loss of organ weight such as a loss ofbone or muscle mass due to a decrease in tissue protein.

In one embodiment, the terms “muscle wasting” or “muscular wasting”,refer to the progressive loss of muscle mass and/or to the progressiveweakening and degeneration of muscles, including the skeletal orvoluntary muscles which control movement, cardiac muscles which controlthe heart, and smooth muscles. In one embodiment, the muscle wastingcondition or disorder is a chronic muscle wasting condition or disorder.“Chronic muscle wasting” is defined herein as the chronic (i.e.persisting over a long period of time) progressive loss of muscle massand/or to the chronic progressive weakening and degeneration of muscle.

The loss of muscle mass that occurs during muscle wasting can becharacterized by a muscle protein breakdown or degradation, by muscleprotein catabolism. Protein catabolism occurs because of an unusuallyhigh rate of protein degradation, an unusually low rate of proteinsynthesis, or a combination of both. Protein catabolism or depletion,whether caused by a high degree of protein degradation or a low degreeof protein synthesis, leads to a decrease in muscle mass and to musclewasting. The term “catabolism” has its commonly known meaning in theart, specifically an energy burning form of metabolism.

Muscle wasting can occur as a result of pathology, disease, condition ordisorders, including disorders for treatment via the methods of thisinvention, such as, for example, end stage renal failure.

In some embodiments, the present invention provides a method forprevention of statin induced rhabdomyolysis. In some embodiments, thepresent invention provides a method for prevention of statin inducedrhabdomyolysis, organ failure or insufficiency. In some embodiments, thepresent invention provides a method for prevention of statin inducedkidney or liver failure or insufficiency. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and a statin.

In one embodiment, the wasting disease is cachexia or involuntary weightloss in a subject. In another embodiment, the present invention providesa method of treating, preventing, inhibiting, reducing or suppressingmuscle wasting in a subject suffering from a kidney disease. In oneembodiment, the present invention provides a method of treating,preventing, inhibiting, reducing or suppressing protein catabolism in asubject suffering from a kidney disease or disorder,

Cachexia is weakness and a loss of weight caused by a disease or as aside effect of illness. Long term hospitalization due to illness orinjury, or disuse deconditioning that occurs, for example, when a limbis immobilized, can also lead to muscle wasting. Studies have shown thatin patients suffering injuries, chronic illnesses, burns, trauma orcancer, who are hospitalized for long periods of time, there is along-lasting unilateral muscle wasting, with a consequent decrease inbody mass. Nervous system injury, for example, spinal cord injury, asdescribed further herein, may be a contributory factor, as well.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a wastingdiseases or disorders in a subject. In another embodiment, the wastingdiseases and disorders include inter alia: a) acquired immunodeficiencysyndrome (AIDS) wasting; b) wasting associated with bed rest; c)bulimia, and/or wasting associated with bulimia; d) cachexia; e) cancercachexia; f) HIV wasting; g) reduce cachexia and protein loss due toprolonged critical illness, pulmonary dysfunction, ventilatordependency, aging, AIDS, trauma, surgery, congestive heart failure,cardiac myopathy, burns, cancer, chronic obstructive pulmonary disease(COPD), eating disorders such bulimia, anorexia nervosa, loss ofappetite, starvation, and/or depression.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with invalid statesin a subject. In one embodiment, the invalid state is post-poliosyndrome. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention and animmunomodulating agent, an antidiabetic agent, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating the central nervous system, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, vitamins, or a combination thereof.

In some embodiments, this invention provides for adjunct therapies withthe compounds of this invention. For example, and in one embodiment, inthe treatment of diseases, disorders or conditions whereby exercise andrestricted diets are useful, the administration of the compounds of thisinvention are included in such treatment regimens. For example, and inone embodiment, the adjunct therapy of treatment with a compound of thisinvention in conjunction with restricted diet and/or exercise may be atherapy for treating insulin resistance, glucose intolerance, weightloss, diabetes, cardiovascular disease, metabolic syndrome, cancer,muscle wasting, and others as will be appreciated by one skilled in theart.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a hypogonadalstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced hypogonadal state in a subject. In someembodiments, hypogonadism is caused by treatments which alter thesecretion of hormones from the sex glands in both women and men. In someembodiments, hypogonadism may be “primary” or “central”. In primaryhypogonadism, the ovaries or testes themselves do not function properly.In some embodiments, hypogonadism may be induced by surgery, radiation,genetic and developmental disorders, liver and kidney disease,infection, or certain autoimmune disorders. In some embodiments,menopause is a form of hypogonadism. Menopause may cause, in someembodiments, amenorrhea, hot flashes, vaginal dryness, or irritabilitydue to woman's estrogen levels fall. In one embodiment, the methodcomprises administering to a subject a composition comprising a compoundof this invention and an anti-cancer agent, an immunomodulating agent,an antidiabetic agent, an agent treating the cardiovascular system, anagent treating the gastrointestinal system, an agent treating thecentral nervous system, an agent treating a metabolic disease, an agenttreating a wasting disease, a gene therapy agent, an agent treating theendocrine system, an agent treating a dermatological disorder, ananti-infective agent, an agent treating the liver, an agent treating thekidney, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with osteopenic statein a subject. In one embodiment, the present invention provides a methodfor treating, reducing the incidence, delaying the onset or progression,or reducing and/or abrogating the symptoms associated with apharmacotherapy induced osteopenic state in a subject. In someembodiments, osteopenia is a mild thinning of the bone mass. In someembodiments, osteopenia is a precursor to osteoporosis. In someembodiments osteopenia is defined as a bone density between one standarddeviation (SD) and 2.5 SD below the bone density of a normal youngadult. In one embodiment, the method comprises administering to asubject a composition comprising a compound of this invention and ananti-cancer agent, an immunomodulating agent, an antidiabetic agent, anagent treating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a sarcopenicstate in a subject. In one embodiment, the present invention provides amethod for treating, reducing the incidence, delaying the onset orprogression, or reducing and/or abrogating the symptoms associated witha pharmacotherapy induced sarcopenic state in a subject. In someembodiments, sarcopenia is a significant loss of muscle mass. In oneembodiment, sarcopenia definition is having a lean body mass less thantwo standard deviation below the mean for normal young adults. In someembodiments, sarcopenia is caused by genetic factors, alteredcirculation, decrease in the capillary:muscle fiber ratio, altered motorneurons, denervation, deterioration of motor end plates, selectivereinnervation of Type I fibers, inflammatory responses causing muscledamage, reduced exercise, malnutrition, low dietary protein intake,vitamin D deficiency, age-related decline in vitamin D, oxidativestress, muscle mitochondrial mutations, changes in specific types ofmuscle fibers, decline in muscle protein, disabling disease, strokes,Alzheimer's disease, Parkinson's disease, osteoporosis, atherosclerosis,diabetes mellitus, hyperinsulimemia, renal failure, or hypogonadism. Inone embodiment, the method comprises administering to a subject acomposition comprising a SARM compound and an anti-cancer agent, animmunomodulating agent, an antidiabetic agent, an agent treating thecardiovascular system, an agent treating the gastrointestinal system, anagent treating the central nervous system, an agent treating a metabolicdisease, an agent treating a wasting disease, a gene therapy agent, anagent treating the endocrine system, an agent treating a dermatologicaldisorder, an anti-infective agent, an agent treating the liver, an agenttreating the kidney, vitamins, or a combination thereof.

In some embodiments, the present invention provides a method fortreating, reducing the incidence, delaying the onset or progression, orreducing and/or abrogating the symptoms associated with a combination ofdiseases and/or disorders in a subject as described hereinabove. In oneembodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins, or acombination thereof.

It is to be understood that any method of this invention, as hereindescribed, encompasses the administration of a compound as hereindescribed, or a composition comprising the same, to the subject, inorder to treat the indicated disease, disorder or condition. The methodsas herein described each and/or all may further comprise administrationof an additional therapeutic agent as herein described, and as will beappreciated by one skilled in the art.

In some embodiments, the present invention provides a method forenhanced production such as milk, sperm, or egg. In some embodiments,the present invention provides a method for enhanced production of leanmeats or eggs. In some embodiments, the present invention provides amethod for increased productivity of feeds or stud livestock, forexample, increased sperm count, improved morphology of sperm, etc. Insome embodiments, the present invention provides a method for expandingthe productive life of farm animals, for example, egg-laying hens,milk-producing cows, etc, and/or enhanced herd health, for example,improved immune clearance, stronger animals.

In one embodiment, the method comprises administering to a subject acomposition comprising a compound of this invention and an anti-canceragent, an immunomodulating agent, an antidiabetic agent, an agenttreating the cardiovascular system, an agent treating thegastrointestinal system, an agent treating the central nervous system,an agent treating a metabolic disease, an agent treating a wastingdisease, a gene therapy agent, an agent treating the endocrine system,an agent treating a dermatological disorder, an anti-infective agent, anagent treating the liver, an agent treating the kidney, vitamins,nutritional additives, hormones, each and/or all as herein described, orany other therapeutic agent as herein described, or a combinationthereof.

In another embodiment, this invention provides methods of treatment ofcystic fibrosis and induced hypogonadal states as a result of the same,epilepsy and induced hypogonadal and/or hypermetabolic states as aresult of the same, hereditary angioedema, lupus erythematosus anddecreased BMD as a result of the same, alcohol and smoking inducedosteoporosis, in a subject the methods comprising administering a SARMas herein described to the subject.

In another embodiment, this invention provides methods of treatment ofpolio and post-polio syndrome and other invalid states, statin inducedrhabdomyolysis, statin-induced muscle weakness, statin-induced organfailure or insufficiency, in a subject, the methods comprising theadministration of a compound as herein described, optionally with astatin, as appropriate, as will be appreciated by one skilled in theart, and/or with any therapeutic agent.

In another embodiment, this invention provides a method of treatingopioid induced androgen deficiency (OPIAD), the method comprisingadministering to the subject a compound as herein described, andoptionally opiates, opioids, narcotics, etc. methadone, long-actingopiates/opioids such as Kadian, extended release morphines, allopiates/opioids/narcotics agents approved by FDA, opiates/opioids usedin treatment of heroin addiction, opiates/opioids used in the treatmentof chronic pain of malignancy, opiates/opioids used in the treatmentnon-malignant of chronic pain syndromes.

In another embodiment, this invention provides a method of treating anervous system disease, disorder or condition, the method comprisingadministering to the subject a compound as herein described, andoptionally anti-psychotics, such as, for example, zotepine, haloperidol,amisulpride, risperidone, other D2 dopamine receptor antagonists;anti-epileptics, such as valproic acid, carbamazepine, oxcarbamazepine,etc. or combinations thereof.

In another embodiment, this invention provides a method of treating ahormone dependent disease, disorder or condition, the method comprisingadministering to the subject a compound as herein described, andoptionally chemotherapeutics agents and therapies (methotrexate,cyclophosphamide, ifosfamide, adriamycin, doxorubicin, glucocorticoids,cyclosporine, L-thyroxine, SERMs, anti-inflammatory, fulvestrant, GnRHagents, ADT, discontinuation of hormone replacement therapy, cranialirradiation, peripheral irradiation, etc.; prolactinemia-inducingpharmacotherapeutics (serotonergic antidepressants acting through 5HT2receptors, selective serotonin reuptake inhibitors, monoamine oxidaseinhibitors, tricyclic antidepressants, antihypertensives such asmethyldopa, reserpine, clonidine, and verapamil; antidopaminergicanti-emetics such as metoclopramide, H2 receptor antagonists such ascimetidine and ranitidine, estrogens, amphetamines, AR partialantagonists (ketoconazole, spironolactone, eplerenone)

In another embodiment, the compounds of this invention and compositionsas described herein are useful in promoting or speeding recoveryfollowing a surgical procedure.

In one embodiment, the present invention provides a use of a compound asdescribed herein for reducing a fat mass in a subject. In anotherembodiment the invention provides such methods for use of the compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same.

In another embodiment, this invention provides for the use of a compoundas described herein or its prodrug, analog, isomer, metabolite,derivative, pharmaceutically acceptable salt, pharmaceutical product,polymorph, crystal, impurity, N-oxide, hydrate or any combinationthereof, or a composition comprising the same, in treating abdominal fataccumulation; treating obese sarcopenia; improving body composition;lowering body fat content; lowering fat mass; improving blood lipidprofile, increasing muscle mass/strength/function; increasing bonemass/BMD/strength/function; lowering body fat; congenitalhyperinsulinemia; Cushing's disease (hypercortisolemia); obesity ordiabetes associated with a metabolic syndrome in a subject.

In another embodiment, the subject has a hormonal imbalance, disorder,or disease. In another embodiment the subject has menopause.

In one embodiment, the present invention provides a use of a compound asdescribed herein for increasing a lean mass in a subject. In anotherembodiment such use comprises administration of a compound as describedherein or its prodrug, analog, isomer, metabolite, derivative,pharmaceutically acceptable salt, pharmaceutical product, polymorph,crystal, impurity, N-oxide, hydrate or any combination thereof.

In one embodiment the subject has a hormonal imbalance, disorder, ordisease. In another embodiment the subject has menopause.

Example 15 demonstrates that a compound of formula (I) is anabolic yetminimally androgenic, thus such compounds may be useful in treatingpatient groups in which androgens were contraindicated in the past.Compound of formula (I) was shown to stimulate muscle growth, whether inthe presence or absence of testosterone while exertinganti-proliferative effects on the prostate, thus, in one embodiment, themethods of this invention provide for restoring lost muscle mass inpatients with sarcopenia or cachexia.

In one embodiment, the compounds as herein described alter the levels ofleptin in a subject. In another embodiment, the compounds as hereindescribed decrease the levels of leptin. In another embodiment, thecompounds as herein described increase the levels of leptin in asubject. Leptin is known to have an effect on appetite on weight loss inobese mice, and thus has been implicated in obesity.

The compounds as herein described, in one embodiment, affectcirculating, or in another embodiment, tissue levels of leptin. In oneembodiment, the term ‘levels of leptin’ refers to the serum level ofleptin. As contemplated herein, the compounds of the present inventionhave an effect on leptin in vitro and in vivo. Leptin levels can bemeasured by methods known to one skilled in the art, for example bycommercially available ELISA kits. In addition, leptin levels may bedetermined in in vitro assays, or in in vivo assays, by any method knownto a person skilled in the art.

Since leptin is implicated in controlling appetite, weight loss, foodintake, and energy expenditure, modulating and/or controlling the levelsof leptin is a useful therapeutic approach in treating preventing,inhibiting or reducing the incidence of obesity in subjects sufferingfrom obesity. Modulating the level of leptin can result in a loss ofappetite, a reduction of food intake, and an increase in energyexpenditure in the subject, and thus may contribute to the control andtreatment of obesity.

The term “obesity” is defined, in one embodiment, as an increase in bodyweight beyond the limitation of skeletal and physical requirement, asthe result of excessive accumulation of fat in the body.

The term “obesity-associated metabolic disorder” refers, in oneembodiment, to a disorder which results from, is a consequence of, isexacerbated by or is secondary to obesity. Non-limiting examples of sucha disorder are osteoarthritis, Type II diabetes mellitus, increasedblood pressure, stroke, and heart disease.

Cholesterol, triacylglycerol and other lipids are transported in bodyfluids by lipoproteins which may be classified according to theirdensity, for example, the very low density lipoproteins (VLDL),intermediate density lipoproteins (IDL), low density lipoproteins (LDL)and high density lipoproteins (HDL).

It has been shown that high levels of LDL-cholesterol in the bloodcorrelate with atherosclerosis which is a progressive diseasecharacterized in part by sedimentation of lipids in inner walls ofarteries, particularly of coronary arteries. It has also been shown thata high blood level of LDL-cholesterol correlates with coronary heartdisease. Also, a negative correlation exists between blood levels of HDLcholesterol and coronary heart disease.

The level of total cholesterol in blood, which is the sum ofHDL-cholesterol, LDL-cholesterol, VLDL-cholesterol andchylomicron-cholesterol, is not necessarily predictive of the risk ofcoronary heart disease and atherosclerosis.

The correlation between atherosclerosis and LDL cholesterol levels,however, is much higher than a similar correlation betweenatherosclerosis and total serum cholesterol levels.

In one embodiment, this invention provides methods of use of thecompounds as herein described for improving the lipid profile and/orreducing the circulating lipid levels in a subject. In some embodiments,according to this aspect of the invention, the subject suffers from oneor more conditions selected from the group consisting of:atherosclerosis and its associated diseases, premature aging,Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, and hyperglycemia, andthe invention provides for the administration of a compound orcomposition comprising the same, as herein described, which in someembodiments positively affects a lipid profile in the subject, which isone means by which the method is useful in treating the indicateddiseases, disorders and conditions.

In one embodiment the invention provides for the treatment ofatherosclerosis and its associated diseases, such as for example,cardiovascular disorders, cerebrovascular disorders, peripheral vasculardisorders, intestinal vascular disorders, or combinations thereof.

In one embodiment cardiovascular disorders comprise of hypertention(HTN), coronary artery disease (CAD) or myocardial perfusion. In anotherembodiment this invention provides methods of use of the SARM compoundsas herein described for promoting aortic smooth muscle cellproliferation. In another embodiment this invention provides methods ofuse of the compounds as herein described for treating arteriosclerosis.In another embodiment this invention provides methods of use of thecompounds as herein described for lowering blood pressure. In anotherembodiment this invention provides methods of use of the compounds asherein described for treating cardiac diseases and disorders comprisingcardiomyopathy, cardiac dysfunctions such as, myocardial infarction,cardiac hypertrophy and cognitive heart failure. In another embodimentthis invention provides methods of use of the compounds as hereindescribed for cardioprotection comprising cardioprotection in insulinresistance; treating diabetes type I and II, metabolic syndrome,syndrome X and/or high blood pressure.

In one embodiment, the invention provides a method of treating,preventing, reducing the risk of mortality from cardiovascular and/orcerebrovascular disease in a subject, comprising administering acompound of formula (I) or its prodrug, ester, analog, isomer,metabolite, derivative, pharmaceutically acceptable salt, pharmaceuticalproduct, polymorph, crystal, impurity, N-oxide, hydrate or anycombination thereof, or a pharmaceutical composition comprising thesame. In one embodiment, the compound is characterized by the structureof formula (I).

In one embodiment, compounds of formulae I reduce LDL and totalcholesterol levels. In another embodiment the compound of formula (I)reduces LDL and total cholesterol levels in a subject.

In another embodiment, compounds of formulae I are co-administered withHDL-elevating agents. In another embodiment, a compound of formula (I)is co-administered with an HDL-elevating agents. In another embodiment,HDL-elevating agents include niacin. In another embodiment theHDL-elevating agents include fibrates including gemfibrozil (Lopid),thiourea based gemfibrozil analogues, and fenofibrate (TriCor). Inanother embodiment, HDL-elevating agents include statins. In anotherembodiment, HDL-elevating agents include1-hydroxyalkyl-3-phenylthiourea, and analogs thereof.

In one embodiment, this invention provides a method of reducingcirculating lipid levels in a subject, said method comprisingadministering a compound of formula I or its pharmaceutically acceptablesalt, hydrate, N-oxide, or any combination thereof, or a compositioncomprising the same. In one embodiment, the subject suffers fromatherosclerosis and its associated diseases, premature aging,Alzheimer's disease, stroke, toxic hepatitis, viral hepatitis,peripheral vascular insufficiency, renal disease, hyperglycemia, or anycombination thereof.

In one embodiment, this invention provides a method of treatingatherosclerosis and its associated diseases, such as, for example,cardiovascular disorders, cerebrovascular disorders, peripheral vasculardisorders, or intestinal vascular disorders in a subject, the methodcomprising the step of administering to the subject compound of formulaI or its pharmaceutically acceptable salt, hydrate, N-oxide, or anycombination thereof, or a composition comprising the same. The methodmay further comprise co-administration, subsequent or prioradministration with an agent or agents, which are known to be useful intreating cardiovascular disorders, cerebrovascular disorders, peripheralvascular disorders, or intestinal vascular disorders.

In one embodiment, this invention provides a method of improving thedexterity and movement in a subject, for example, by treating arthritisin the subject.

The term “arthritis” refers, in another embodiment, to anon-inflammatory degenerative joint disease occurring chiefly in olderpeople, characterized by degeneration of the articular cartilage,hypertrophy of bones and the margins, changes in the synovial membrane,etc. It is accompanied, in other embodiments, by pain and stiffness,particularly after prolonged activity.

The term “diabetes”, in one embodiment, refers to a relative or absolutelack of insulin leading to uncontrolled carbohydrate metabolism. Mostpatients can be clinically classified as having either insulin-dependentdiabetes mellitus (IDDM or Type-I diabetes) or non-insulin-dependentdiabetes mellitus (NIDDM or Type-II diabetes).

The term “increased blood pressure” or “hypertension” refers, in otherembodiments, to a repeatedly high blood pressure above 140 over 90 mmHg.Chronically-elevated blood pressure can cause blood vessel changes inthe back of the eye, thickening of the heart muscle, kidney failure, andbrain damage.

The term “stroke” refers, in other embodiments, to damage to nerve cellsin the brain due to insufficient blood supply often caused by a burstingblood vessel or a blood clot. The term “heart disease”, in otherembodiments, refers to a malfunction in the heart normal function andactivity, including heart failure.

In addition, androgens have recently been shown to be involved incommitment of mesenchymal pluripotent cells into myogenic lineage and toblock differentiation into adipogenic lineage (Singh et al.,Endocrinology, 2003, Jul. 24). Accordingly, the compounds can be usefulin methods of blocking adipogenesis, and/or altering stem celldifferentiation, as described herein.

In another embodiment, this invention relates to a method of promoting,increasing or facilitating weight loss in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to promote,increase or facilitate weight loss in the subject.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing appetite of a subject, comprisingthe step of administering to the subject a compound as herein describedand/or its analog, derivative, isomer, metabolite, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, prodrug,polymorph, crystal, or any combination thereof, in an amount effectiveto decrease, suppress, inhibit or reduce the appetite of the subject.

In another embodiment, this invention relates to a method of alteringthe body composition of a subject, comprising the step of administeringto the subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to alter the bodycomposition of the subject. In one embodiment, altering the bodycomposition comprises altering the lean body mass, the fat free bodymass of the subject, or a combination thereof.

In another embodiment, this invention relates to a method of alteringlean body mass or fat free body mass of a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alter thelean body mass or fat free body mass of the subject.

In another embodiment, this invention relates to a method of convertingfat to lean muscle in a subject, comprising the step of administering tothe subject a compound as herein described and/or its analog,derivative, isomer, metabolite, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, prodrug, polymorph, crystal,or any combination thereof, in an amount effective to convert fat tolean muscle in the subject.

In another embodiment, this invention relates to a method of treating anobesity-associated metabolic disorder in a subject, comprising the stepof administering to the subject a compound as herein described and/orits analog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to treat theobesity-associated metabolic disorder in the subject.

In another embodiment, this invention relates to a method of preventing,suppressing, inhibiting or reducing an obesity-associated metabolicdisorder in a subject, comprising the step of administering to thesubject a compound as herein described and/or its analog, derivative,isomer, metabolite, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, prodrug, polymorph, crystal, or anycombination thereof, in an amount effective to prevent, suppress,inhibit or reduce the obesity-associated metabolic disorder in thesubject.

In one embodiment, the obesity-associated metabolic disorder ishypertension. In another embodiment, the disorder is osteoarthritis. Inanother embodiment, the disorder is Type II diabetes mellitus. Inanother embodiment, the disorder is increased blood pressure. In anotherembodiment, the disorder is stroke. In another embodiment, the disorderis heart disease.

In another embodiment, this invention relates to a method of decreasing,suppressing, inhibiting or reducing adipogenesis in a subject,comprising the step of administering to the subject a compound as hereindescribed and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal, or any combination thereof.

In another embodiment, this invention relates to a method of alteringstem cell differentiation in a subject, comprising the step ofadministering to the subject a compound as herein described and/or itsanalog, derivative, isomer, metabolite, pharmaceutically acceptablesalt, pharmaceutical product, hydrate, N-oxide, prodrug, polymorph,crystal, or any combination thereof, in an amount effective to alterstem cell differentiation in the subject.

In one embodiment, the compounds as herein described are useful in a)treating, preventing, suppressing, inhibiting, or reducing obesity; b)promoting, increasing or facilitating weight loss; c) decreasing,suppressing, inhibiting or reducing appetite; d) altering the bodycomposition; e) altering lean body mass or fat free body mass; f)converting fat to lean muscle; g) treating, preventing, suppressing,inhibiting, or reducing an obesity-associated metabolic disorder, forexample hypertension, osteoarthritis, diabetes mellitus, maturity onsetdiabetes of the young (MODY), increased blood pressure, stroke, or heartdisease; h) decreasing, suppressing, inhibiting or reducingadipogenesis; i) altering stem cell differentiation; and/or j) alteringthe level of leptin.

In one embodiment, the compounds as herein described find utility intreating or halting the progression of, or treating symptoms ofdiabetes. In another embodiment, the compounds as herein described areuseful in treating co-morbidities related to diabetes. These conditionsinclude: hypertension (HTN), cerebrovascular disease, atheroscleroticcoronary artery disease, macular degeneration, diabetic retinopathy (eyedisease) and blindness, cataracts—systemic inflammation (characterizedby elevation of inflammatory markers such as erythrocyte sedimentationrate or C-reactive protein), birth defects, pregnancy related diabetes,pre-ecclampsia and hypertension in pregnancy, kidney disease (renalinsufficiency, renal failure etc.), nerve disease (diabetic neuropathy),superficial and systemic fungal infections, congestive heart failure,gout/hyperuricemia, obesity, hypertriglyceridemia, hypercholesterolemia,fatty liver disease (non-alcoholic steatohepatitis, or NASH), anddiabetes-related skin diseases such as Necrobiosis LipoidicaDiabeticorum (NLD), Blisters of diabetes (Bullosis Diabeticorum),Eruptive Xanthomatosis, Digital Sclerosis, Disseminated GranulomaAnnulare, and Acanthosis Nigricans.

In one embodiment this invention provides a method of treating,suppressing, inhibiting or reducing the incidence of (a) diabetes typeI; (b) diabetes type II; (c) glucose intolerance; (d) hyperinsulinemia;(e) insulin resistance (f) nephropathy; (g) diabetic neuropathy; (h)diabetic retinopathy (i) fatty liver conditions (j) MODY and (k)cardiovascular disease in a human subject, comprising the step ofadministering to said subject a compound of formula I.

In some embodiments, the compounds as herein described and/orcompositions comprising the same may be used for applications in, ortreating diseases or conditions associated with a subject havingdiabetes. In one embodiment, the subject for whom treatment is soughtvia the methods of this invention is one with diabetic I. Type Idiabetes is characterized by autoimmune destruction of pancreaticbeta-cells. Markers of immune destruction of the beta-cell are presentat the time of diagnosis in 90% of individuals and include antibodies tothe islet cell (ICAs), to glutamic acid decarboxylase (GAD), and toinsulin (IAAs). While this form of diabetes usually occurs in childrenand adolescents, it can occur at any age. Younger individuals typicallyhave a rapid rate of beta-cell destruction and present withketoacidosis, while adults often maintain sufficient insulin secretionto prevent ketoacidosis for many years. Eventually, all type I diabeticpatients require insulin therapy to maintain normoglycemia.

In one embodiment, this invention provides a method of treating diabetestype II. Type II diabetes is characterized by insulin resistance and atsome stage in pathogenesis of the disease, a relative deficiency ofinsulin secretion. In absolute terms, the plasma insulin concentration(both fasting and meal-stimulated) usually is increased, although“relative” to the severity of insulin resistance, the plasma insulinconcentration is insufficient to maintain normal glucose homeostasis.With time, however, there is progressive beta cell failure and absoluteinsulin deficiency ensues. Most individuals with type II diabetesexhibit intra abdominal (visceral) obesity, fatty liver, which isclosely related to the presence of insulin resistance. The patient'sliver becomes insulin resistant and glycogen breakdown is uncontrolledand the result is increased and unphysiological glucose delivery to thebloodstream. The liver generated cholesterol and VLDL particles is alsouncontrolled. In addition, hypertension, dyslipidemia (high triglycerideand low HDL-cholesterol levels; postprandial hyperlipemia), and elevatedPAI-1 levels often are present in these individuals. This clustering ofabnormalities is referred to as the “insulin resistance syndrome”, orthe “metabolic syndrome” or obesity related disorders. Because of theseabnormalities, patients with type II diabetes are at increased risk ofdeveloping macrovascular complications such as myocardial infarction andstroke.

In one embodiment, this invention provides a method of treating diabeticnephropathy. Diabetic nephropathy is a complication of diabetes thatevolves early, typically before clinical diagnosis of diabetes is made.The earliest clinical evidence of nephropathy is the appearance of lowbut abnormal levels (>30 mg/day or 20 μg/min) of albumin in the urine(microalbuminuria), followed by albuminuria (>300 mg/24 h or 200 μg/min)that develops over a period of 10-15 years. In patients with type Idiabetes, diabetic hypertension typically becomes manifest early on, bythe time that patients develop microalbuminuria. Once overt nephropathyoccurs, the glomerular filtration rate (GFR) falls over a course oftimes, which may be several years, resulting in end stage renal disease(ESRD) in diabetic individuals.

In one embodiment, this invention provides a method of treating diabeticneuropathy. Diabetic neuropathy is a family of nerve disorders caused bydiabetes. Diabetic neuropathies cause numbness and sometimes pain andweakness in the hands, arms, feet, and legs. Neurologic problems indiabetes may occur in every organ system, including the digestive tract,heart, and genitalia. Diabetic neuropathies are classified asperipheral, autonomic, proximal, and focal. Peripheral neuropathy causespain or loss of feeling in the toes, feet, legs, hands, and arms.Autonomic neuropathy causes changes in digestion, bowel and bladderfunction, sexual response, and perspiration and can also affect thenerves that serve the heart and control blood pressure. Proximalneuropathy causes pain in the thighs, hips, or buttocks and leads toweakness in the legs. Focal neuropathy results in the sudden weakness ofone nerve, or a group of nerves, causing muscle weakness or pain. Anynerve in the body may be affected.

In one embodiment, this invention provides a method of treating diabeticretinopathy. The effect of diabetes on the eye is called diabeticretinopathy. Patients with diabetes are more likely to develop eyeproblems such as cataracts and glaucoma. The affect of diabeticretinopathy on vision varies widely, depending on the stage of thedisease. Some common symptoms of diabetic retinopathy are blurred vision(this is often linked to blood sugar levels), floaters and flashes andsudden loss of vision.

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with glucose intolerance. Glucoseintolerance is a pre-diabetic state in which the blood glucose is higherthan normal but not high enough to warrant the diagnosis of diabetes.

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with hyperinsulinemia. Hyperinsulinemiais a sign of an underlying problem that is causing the pancreas tosecrete excessive amounts of insulin. The most common cause ofhyperinsulinemia is insulin resistance, a condition in which your bodyis resistant to the effects of insulin and the pancreas tries tocompensate by making more insulin. hyperinsulinemia is associated withtype II diabetes

In one embodiment, the subject for whom treatment is sought via themethods of this invention is one with insulin resistance. Insulinresistance is a condition in which normal amounts of insulin areinadequate to produce a normal insulin response from fat, muscle andliver cells. Insulin resistance in fat cells results in hydrolysis ofstored triglycerides, which elevates free fatty acids in the bloodplasma. Insulin resistance in muscle reduces glucose uptake whereasinsulin resistance in liver reduces glucose storage, with both effectsserving to elevate blood glucose. High plasma levels of insulin andglucose due to insulin resistance often leads to the metabolic syndromeand type II diabetes.

Diabetes and the liver obesity is typically associated with elevatedlevels of free fatty acid (FFAs) that promote lipid accumulation andinsulin resistance in target tissues, i.e. reduced action of insulinprimarily in skeletal muscle and liver. A prominent role of insulin isto reduce glucose output from the liver. FFAs stimulate hepaticgluconeogenesis which per se does not lead to increased hepatic glucoseoutput as long as it is paralleled by a decrease in hepaticglycogenolysis, a compensatory process referred to as “hepaticautoregulation”. FFAs stimulate insulin secretion and insulin blocksglycogenolysis in part by inhibiting secretion of glucagon, an inducerof glycogenolysis. However, long-term elevated levels of FFAs leads tohepatic insulin resistance and thus breakdown of hepatic autoregulation,resulting in increased hepatic glucose production and development oftype II diabetes. Fatty liver and hepatic insulin resistance is a majordriving force behind hyperglycemia and type II diabetes.

In one embodiment, this invention provides methods that inhibit(improve) the fatty liver, resulting in that the insulin resistance inthe liver is inhibited (improved) and thereby solving the basic problemin type II diabetes.

In another embodiment, the diabetes is a type I diabetes. In anotherembodiment, the diabetes is a type II diabetes.

In one embodiment, this invention provides a method of treatingsuppressing, inhibiting or reducing the incidence of diabetes is a humansubject, comprising the step of administering to said subject a compoundof formula I or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof.

In another embodiment, the diabetes is a Type I diabetes. In anotherembodiment, the diabetes is a type II diabetes.

In one embodiment, this invention provides a method of treating a humansubject having glucose intolerance, comprising the step of administeringto said subject compound of formula I or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof.

In one embodiment, this invention provides a method of treatinghyperinsulinemia in a human subject, comprising the step ofadministering to said subject a compound of formula I or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating insulinresistance in a human subject, comprising the step of administering tosaid subject the compound of formula I or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof.

In one embodiment, this invention provides a method of treating diabeticnephropathy in a human subject, comprising the step of administering tosaid subject a selective androgen receptor modulator compound of formula(I) or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, hydrate, N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating diabeticneuropathy in a human subject, comprising the step of administering tosaid subject compound of formula (I) or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof.

In one embodiment, this invention provides a method of treating diabeticretinopathy in a human subject, comprising the step of administering tosaid subject a compound of formula (I) or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, hydrate, N-oxide, or anycombination thereof.

In one embodiment, this invention provides a method of treating fattyliver conditions in a human subject, comprising the step ofadministering to said subject a selective androgen receptor modulatorcompound of formula (I) or its isomer, pharmaceutically acceptable salt,pharmaceutical product, hydrate, N-oxide, or any combination thereof.

In one embodiment, this invention provides a method of treating avascular disease in a human subject, comprising the step ofadministering to said subject a compound of formula (I) or its isomer,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, or any combination thereof.

In one embodiment this invention provides a method for a) treating,preventing, suppressing inhibiting atherosclerosis b) treating,preventing, suppressing inhibiting liver damage due to fat depositscomprising the step of administering to the subject a compound asdescribed herein and/or its analog, derivative, isomer, metabolite,pharmaceutically acceptable salt, pharmaceutical product, hydrate,N-oxide, prodrug, polymorph, crystal, or any combination thereof, or acomposition comprising the same, in an amount effective to treat,prevent or inhibit atherosclerosis and liver damage due to fat deposit.

In one embodiment, the compound as described herein is useful in a)treating, preventing, suppressing, inhibiting, or reducingatherosclerosis; b) treating, preventing, suppressing inhibiting liverdamage due to fat deposits.

In one embodiment atherosclerosis refers to a slow, complex disease thatmay begin with damage to the innermost layer of the artery. In anotherembodiment the causes of damage to the arterial wall may include a)elevated levels of cholesterol and in the blood; b) high blood pressure;c) tobacco smoke d) diabetes. In another embodiment, the condition istreatable in a smoker, despite the fact that tobacco smoke may greatlyworsen atherosclerosis and speed its growth in the coronary arteries,the aorta and arteries in the legs. Similarly, in another embodiment,the methods of this invention may be useful in treating subjects with afamily history of premature cardiovascular disease who have an increasedrisk of atherosclerosis.

In one embodiment, liver damage due to fat deposits refer to thebuild-up of fat in the liver cells forming a fatty liver which may beassociated with or may lead to inflammation of the liver. This can causescarring and hardening of the liver. When scarring becomes extensive, itis called cirrhosis.

In another embodiment the fat accumulates in the liver as obesity. Inanother embodiment fatty liver is also associated with diabetesmellitus, high blood triglycerides, and the heavy use of alcohol. Inanother embodiment fatty Liver may occur with certain illnesses such astuberculosis and malnutrition, intestinal bypass surgery for obesity,excess vitamin A in the body, or the use of certain drugs such asvalproic acid (trade names: Depakene/Depakote) and corticosteroids(cortisone, prednisone). Sometimes fatty liver occurs as a complicationof pregnancy.

In one embodiment, subjects with kidney disease, in particular malesubjects with end-stage renal disease (ESRD) suffer from hypogonadism,with some having concomitant moderate to severe protein-energymalnutrition (PEM), which leads to higher required doses of EPO, lowerQOL scores, and higher mortality. Many have other symptoms associatedwith hypogonadism, including fatigue, lack of apetite, muscle weakness,etc. In some embodiments, the treatment methods of this invention areuseful in treating symptoms associated with hypogonadism, brought aboutin the subject by the kidney disease or disorder.

In one embodiment, diabetic nephropathy is a complication of diabetesthat evolves early, typically before clinical diagnosis of diabetes ismade. The earliest clinical evidence of nephropathy is the appearance oflow but abnormal levels (>30 mg/day or 20 μg/min) of albumin in theurine (microalbuminuria), followed by albuminuria (>300 mg/24 h or 200μg/min) that develops over a period of 10-15 years. In patients withtype I diabetes, diabetic hypertension typically becomes manifest earlyon, by the time that patients develop microalbuminuria. Once overtnephropathy occurs, the glomerular filtration rate (GFR) falls over acourse of times, which may be several years, resulting in End StageRenal Disease (ESRD) in diabetic individuals.

Hypertension is another comorbid factor for renal disease. In someembodiments, treatment of renal disease according to the presentinvention may comprise concomitant treatment with a compound of thisinvention and an agent which treats hypertension.

Androgen-dependent conditions which may be treated with the compoundsand/or compositions as herein described, comprising the methods of thepresent invention include those conditions which are associated withaging. In one embodiment, the compound as described herein is useful ina) Age-related functional decline (ARFD); b) reversal or prevention ofARFD; c) reversal or prevention of ARFD in elderly d) reversal orprevention of ARFD-induced sarcopenia or osteopenia; e) andropause,andropausal vasomotor symptoms, f) andropausal gynecomastia, musclestrength/function; g) bone strength/function; h) anger; i) asthenia; j)chronic fatigue syndrome; k) cognitive impairment; and/or l) improvingcognitive function.

In one embodiment, the compound as described herein is useful intreating inflammation and related disorders such as a) prevention,treatment, or reversal of arthritis; b) prevention, treatment, orreversal of an arthritic condition such as Behcet's disease (autoimmunevasculitis), bursitis, calcium pyrophosphate dihydrate crystaldeposition disease (or pseudogout) (CPPD), carpal tunnel syndrome,connective tissue disorders, Crohn's diseases, Ehlers-Danlos syndrome(EDS), fibromyalgia, gout, infectious arthritis, inflammatory boweldisease (IBD), juvenile arthritis, systemic lupus erythematosus (SLE),Lyme's disease, Marfan syndrome, myositis, osteoarthritis, polyarteritisnodosa, polymyalgia rheumatica, psoriasis, psoriatic arthritis,Raynaud's phenomenon, reflex sympathetic dystrophy syndrome, Reiter'ssyndrome, rheumatoid arthritis, scleroderma, Sjögrens' syndrome,tendonitis or ulcerative colitis; c) preventing, treatment, or reversingan autoimmune disease.

In one embodiment, the compound as described herein is useful inprevention of iatrogenic effects comprising acute fatigue syndrome(post-surgical) or androgen-deprivation therapy (ADT) induced sideeffects such as reduced muscle mass, reduced muscle strength, frailty,hypogonadism, osteoporosis, osteopenia, decreased BMD and/or decreasedbone mass.

In one embodiment, the compounds and/or compositions and/or methods ofuse thereof are for the treatment of human subjects, wherein, in oneembodiment, the subject is male, or in another embodiment, the subjectis female.

In one embodiment, the methods of the present invention compriseadministering a compound of this invention as the sole activeingredient. However, also encompassed within the scope of the presentinvention are methods for diabetes and related disorders, hormonetherapy, dry eye, obesity, treating prostate cancer, delaying theprogression of prostate cancer, and for preventing and/or treating therecurrence of prostate cancer, male contraception; treatment ofosteoporosis, treatment of conditions associated with ADIF and fortreatment and/or prevention of chronic muscular wasting which compriseadministering the compounds in combination with one or more therapeuticagents. These agents include, but are not limited to: LHRH analogs,reversible antiandrogens, antiestrogens, anticancer drugs, 5-alphareductase inhibitors, aromatase inhibitors, progestins, agents actingthrough other nuclear hormone receptors, selective estrogen receptormodulators (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine,bisphosphonate, and one or more additional SARMs.

Thus, in one embodiment, the methods of the present invention compriseadministering the compound of this invention in combination withdiabetes drug such as troglitazone, rosiglitazone, and pioglitazone. Inanother embodiment, the methods of the present invention compriseadministering the compound in combination with an LHRH analog. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with a reversibleantiandrogen. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anantiestrogen. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with ananticancer drug. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with a5-alpha reductase inhibitor. In another embodiment, the methods of thepresent invention comprise administering the compound, in combinationwith an aromatase inhibitor. In another embodiment, the methods of thepresent invention comprise administering the compound, in combinationwith a progestin. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anagent acting through other nuclear hormone receptors. In anotherembodiment, the methods of the present invention comprise administeringthe compound, in combination with a selective estrogen receptormodulators (SERM). In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with aprogesterone. In another embodiment, the methods of the presentinvention comprise administering the compound, in combination with anestrogen. In another embodiment, the methods of the present inventioncomprise administering the compound, in combination with a PDE5inhibitor. In another embodiment, the methods of the present inventioncomprise administering the compound, in combination with apomorphine. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with a bisphosphonate. Inanother embodiment, the methods of the present invention compriseadministering the compound, in combination with one or more additionalSARMs. In some embodiments, the methods of the present inventioncomprise combined preparations comprising the compound and an agent asdescribed hereinabove. In some embodiments, the combined preparationscan be varied, e.g., in order to cope with the needs of a patientsubpopulation to be treated or the needs of the single patient whichdifferent needs can be due to the particular disease, severity of thedisease, age, sex, or body weight as can be readily determined by aperson skilled in the art. In some embodiments, the methods of thepresent invention comprise personalized medicine methods which treat theneeds of a single patient. In one embodiment, different needs can be dueto the particular disease, severity of the disease, the overall medicalstate of a patient, or the age of the patient. In some embodiments,personalized medicine is the application of genomic data to bettertarget the delivery of medical interventions. Methods of personalizedmedicine, in some embodiments, serve as a tool in the discovery andclinical testing of new products of the present invention. In oneembodiment, personalized medicine involves the application of clinicallyuseful diagnostic tools that may help determine a patient'spredisposition to a particular disease or condition. In someembodiments, personalized medicine is a comprehensive approach utilizingmolecular analysis of both patients and healthy individuals to guidedecisions throughout all stages of the discovery and development ofpharmaceuticals and diagnostics; and applying this knowledge in clinicalpractice for a more efficient delivery of accurate and qualityhealthcare through improved prevention, diagnosis, treatment, andmonitoring methods.

In some embodiments, the compound of formula (I) may be administered inan amount effective to regulate fertility during the female reproductivecycle of an animal or human, or in some embodiments, to controlirregularities in the human menstrual cycle or to synchronize or repressthe fertile periods of commercial animals (e.g., fish, cows, sheep,pigs, goats, or chickens), laboratory animals (e.g., apes, chimpanzees,rats, mice, or guinea pigs), or domestic animals (dogs, cats, ferrets,birds, rabbits, or horses). In some embodiments, the compound of formula(I) may be administered in an amount effective to lessen menstrual flow,thereby being useful in the treatment or prevention of anemia anddysmenorrhea. In some embodiments, the compound of formula (I) may beadministered in an amount effective for the prevention or treatment ofpremenstrual syndrome, endometriosis, leiomyoma (uterine fibroids),and/or ovarian cysts. In addition, in a subject that has or haspreviously had pelvic inflammatory disease, in which scarring of thefallopian tubes may have occurred, the compound of formula (I) may beused to lessen the chance that a tubal pregnancy may occur.

In some embodiments, the compound of formula (I) may be administered inan amount effective to prevent pregnancy. Such administration, in someembodiments, may be prior to ovulation or prior to coitus, or afterovulation or after coitus. In some embodiments, such administrationinhibits implantation of an embryo in the subject or in someembodiments, inhibits ovulation in the subject.

In some embodiments, the compound of formula (I) may be administered inan amount effective to induce cervical ripening in a female. Thecervical ripening may be preparatory to labor and delivery of offspring,or preparatory to dilatation and curettage. In another embodiment, suchadministration is carried out in order to induce expulsion of an embryoor fetus from the subject.

It is to be understood that any use of any of the compounds as hereindescribed may be used in the treatment of any disease, disorder orcondition as described herein, and represents an embodiment of thisinvention.

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way,however, be construed as limiting the broad scope of the invention.

EXAMPLES Example 1 Synthesis of Compound XIII

2-substituted acrylic acid (compound 46) is reacted with4-cyano-3-trifluoromethyl-aniline followed by epoxidation. An opening ofthe epoxide ring with p-CN-phenol in the presence of potassium carbonateyields compound XIII, as presented in FIG. 1B.

Example 2 Synthesis of Compound V

4-cyano-3-trifluoromethyl-aniline is reacted with propene-2-sulfonylchloride (51), and subjected to epoxidation followed by opening of theepoxide ring with p-CN-phenol in the presence of potassium carbonate toyield compound V, as presented in FIG. 1C.

Example 3 Synthesis of Compound XI

Oxiranylmethyl-carbamic acid tert-butyl ester (54) was opened withp-CN-phenol to yield compound 55, followed by deprotection with TFA toyield amino alcohol 56. Compound 56 was introduced in an electrophilicsubstitution reaction with 4-fluoro-2-trifluoromethyl-benzonitrile (57)to form compound 58. Oxidation of 58 to corresponding carbonylderivative 59 which was used in further addition reactions to yieldcompound XI which as presented in FIG. 1D.

Example 4 Synthesis of Compound XXXV

4-methylene-tetrahydro-furan-3-ol (61) is prepared from a startingcompound 3,6-Dioxa-bicyclo[3.1.0]hexane (60) as shown in FIG. 1E. It isused in a Mitsunobu type reaction with p-CN-phenol (50) to form compound62. Dihydroxylation with OsO₄, followed by oxidation with NaClO₄ in thepresence of TEMPO radical (2,2,6,6-tetramethylpiperidinyloxy) forms acid64. Compound 64 using thionyl chloride and4-cyano-3-trifluoromethyl-aniline yields compound XXI, as presented inFIG. 1E.

Example 5 Synthesis of Compound XXXVI

Compound 62 is prepared as in Example 4, followed by epoxidation toyield compound 65 as presented in FIG. 1F. An opening of the epoxidering with 4-cyano-3-trifluoromethyl-aniline yields compound XXXVI, aspresented in FIG. 1F.

Example 6 Synthesis of Compound XLVI

4-cyano-3-trifluoromethyl-aniline is reacted with itaconic anhydride(66) to yield intermediate 67. Further epoxidation and opening of theepoxide ring with p-CN-phenol 50 yields compound XLVI as presented inFIG. 1G.

Example 7 Synthesis of Compound XLIII (FIG. 2)

Pyrrolidine-2-carboxylic acid (56) was acylated by Schotten Baumannreaction to obtain methacryloyl pyrrolidine-2-carboxylic acid (57),which was subsequently lactonized in the presence of N-bromosuccinimideto obtain the bromolactone (58). Hydrolysis of the bromolactone (58)using a 24% HBr solution under reflux conditions for 1 h and subsequentwork up and recrystallization in ethyl acetate-hexane mixture gave3-bromo-2-hydroxy-2-methylpropanoic acid (59) in high yields [59:Whitesolid (Yield: 85%) Mp. 108° C. [α]_(D) ²⁵=+10.5 (c=2.5, 10 MeOH) NMR(OH, 300 MHz, DMSO): 1.35 (s, 3H, CH₃), 3.5 (s, 1H, CH), 3.6 (s, 1H,CH), 4.0 (br, 1H, OH) MS: 205 (M+Na⁺) C₄H₇BrO₃ Calcd.: C, 26.25; H, 3.86Found: C, 26.28; H, 3.75].

The hydroxy and carboxyl groups of compound 59 were then protected withtribromoacetaldehyde by cooling to 0° C. under argon atmosphere andconc. sulfuric acid was added drop-wise with stirring. After 2 h thesolution turned dark; the ice bath was removed and the reaction mixturewas stirred overnight at room temperature. The solution was diluted withice and extracted with ethyl acetate, dried over anhydrous sodiumsulfate and concentrated to obtain the compound 60, which appeared aswhite crystals upon recrystallization from ethyl acetate-hexane. [60:White solid (Yield: 89%) Mp. 97° C. NMR (¹H, 300 MHz, CDCl₃): 1.8 (s,3H, CH₃), 3.7 (s, 2H, CH₂), 5.8 (s, 1H, CH) C₆H₆Br₄O₃ Calcd.: C, 16.17;H, 1.36; Found: C, 16.08; H, 1.25]

Compound 60 was dissolved in a 1:1 mixture of 2-propanol and 1M NaOH andwas stirred at room temperature. After 3 h, when no starting materialwas detectable by TLC, 4′-fluorobenzenethiol was added and the reactionmixture was stirred overnight. The reaction mixture was then adjusted topH 1 with conc. HCl, extracted with ethyl acetate and dried overanhydrous sodium sulfate. The organic layer was concentrated to obtainan oil. Flash column chromatography of the reaction mixture inhexane-ethyl acetate-acetic acid mixture followed by recrystallizationin ethyl acetate-hexane afforded colorless needle shaped crystals. Thecompound was hydrolyzed to remove the protecting group, by acidifyingthe reaction mixture with conc. HCl which afforded the chiral hydroxyacid (55) as presented in FIG. 2. [55: White solid (Yield: 65%) M.p. 54°C.; [α]_(D) ²⁵=+24.85 (c=1.0, MeOH) NMR (¹H, 300 MHz, CDCl₃): 1.5 (s,3H, CH₃), 3.2 (d, 1H, CH), 3.4 (d, H, CH), 7.0 (m, 2H, Ar, J=2.0 Hz, 8.9Hz), 7.5 (m, 2H, Ar, J=2.0 Hz, 8.9 Hz) MS: No parent ion peak C₁₀H₁₁FO₃SCalcd.: C, 52.16; H, 4.82; Found: C, 52.05.59; H, 4.76].

4-Nitro-3-trifluoromethylaniline was converted to the correspondingisothiocyanate (66) by adding thiophosgene and sodium bicarbonate inchloroform medium at 0° C., followed by overnight stirring at roomtemperature. The reaction mixture was concentrated, extracted into ethylacetate dried and evaporated and purified by flash column chromatographyusing hexane-ethyl acetate mixture to afford 66 which appeared as ayellow solid. The hydroxy acid 55 and4-nitro-3-trifluoromethylphenylisothocyanate (66), silvertrifluoroacetate in acetonitrile and triethyl amine were added withstirring and the reaction mixture was heated to reflux for 1 h. Silversulfide was removed by filtration and evaporation of the solvent underreduced pressure, the resulting residue was washed with water, extractedinto ethyl acetate, dried, filtered and concentrated. The desiredproduct, isolated by flash column chromatography using a hexane-ethylacetate mixture appeared as yellow oil. The compound was identified asthe oxazolidinedione (65), as presented in FIG. 2. [65: Yellow coloredoil (Yield: 52%) [α]_(D) ²⁵=+39.7 (c=1.0, MeOH) NMR (¹H, 500 MHz,CDCl₃): 1.8 (s, 3H, CH₃), 3.2 (s, 1H, 20 CH), 3.3 (s, 1H, CH), 6.9 (m,2H, Ar, J=2.0 Hz, 8.9 Hz), 7.2 (m, 2H, Ar, J=2.0 Hz, 8.9 Hz), 7.9 (m,1H, Ar, J=2.1 Hz, 9.0 Hz), 8.0 (m, 1H, Ar, J=0.5 Hz, 2.1 Hz) 8.1 (m, 1H,Ar, J=0.5 Hz, 9.0 Hz) NMR (¹³C, 500 MHz, CDCl₃): 22.8, 43.4, 86.7,117.0, 117.3, 124.4, 124.5, 124.6, 125.0, 126.8, 129.3, 134.2, 134.3,135.3, 164.9, 172.8 MS: No parent ion peak C₁₈H₁₂F₄N₂O₅S Calcd.: C,48.65; H, 2.72; N, 6.30 Found: C, 48.59; H, 2.70; N, 6.31.

HPLC analysis of this product (65) on a n acceptor/donor (R,R)-Whelk-O1chiral column exhibited two peaks in the ratio 70:30 corresponding tothe two enantiomers, with an enantiomeric excess of 40%. The formationof oxazolidinedione must had occurred through the nucleophilicdisplacement of silver sulfide from the imino carbon by the hydroxygroup followed by a concerted cyclic rearrangement as illustrated byintermediate structures (67a) and (67b); a mechanism identical to thatestablished by Shibuya et al. It is contemplated that the excellentseparation of the enantiomers obtained in the aforesaid analyticalchiral column may be extended to the corresponding preparative column inorder to obtain quantitative yields of the enantiomers and therebydetermine their absolute configurations with exciton coupled vibrationalcircular dichroism and infrared spectroscopy along with the aid ofGaussian empirical calculations. It is contemplated further that theoxygen atom of the heterocyclic ring system can be replaced by an aminogroup to obtain enantiomeric hydantoin analogs of bicalutamide whichwould then provide an additional site for hydrogen bonding interactionwith the receptor.

Example 8 Synthesis of Compound XLVIII (FIG. 3)

4-Bromo-2-trifluoromethyl-benzonitrile (74) is prepared from4-cyano-3-trifluoromethyl-aniline (47) via diazotization.4-Bromo-2-trifluoromethyl-benzonitrile (74) is reacted with BuLi toyield Li-derivative (75). 3-Bromo-benzonitrile is reacted with BuLi toyield the Li derivative (77). Alkylation of Li-derivative (77) with(2-bromo-ethoxy)-tert-butyl-dimethyl-silane (78) yields derivative (79)which is converted to acetophenone (80) by MeMgI. Following deprotectionand Mitsunobu reaction with p-CN-phenol forms acetophenone (82).Addition of Li-derivative (75) followed by dehydration yields compoundXLVIII, as presented in FIG. 3.

Example 9 Synthesis of Compound XLIX (FIG. 4)

4-(2-Hydroxy-ethyl)-pyridine-2-carbonitrile (83) is protected bytert-butyl-dimethyl-silane and is transformed into correspondingacetophenone (85) with MeMgI, followed by deprotection and preparationof ether (87). An addition of Li-derivative (75) followed by dehydrationyields compound XLIX as presented in FIG. 4.

Example 10 Synthesis of Compound L (FIG. 6)

Phosphorane (98) is prepared from p-CN-phenol (50) via4-Chloromethoxy-benzonitrile (97) and is used together with3-acetyl-benzaldehyde (99) in a Wittig reaction to give the derivative(100). Subsequent addition of Li derivative (75) as described in Example8 followed by dehydration yields compound L as presented in FIG. 6.

Example 11 Synthesis of Compound LI (FIG. 7)

3-Hydroxymethyl-benzonitrile (101) is protected bytert-butyl-dimethyl-silane to obtain compound (102), followed by MeMgIto obtain the corresponding acetophenone (85). The protection group isremoved, and further reacted with p-CN-phenol to yield (105).Addition ofLi-derivative (75) (as prepared in Example 8) to (105), followed bydehydration yields compound LI, as presented in FIG. 7.

Example 12 Synthesis of Compound LII (FIG. 5)

5-Bromo-2-hydroxy-benzonitrile (88) is protected bytert-butyl-dimethyl-silane to yield compound (89). Compound (89) isreacted with BuLi to yield an Li0 derivative (90), which is furtheralkylated by (2-bromo-ethoxy)-tert-butyl-dimethyl-silane to obtain (91).Compound (91) is reacted with MeMgI to the corresponding acetophenone(92), followed by deprotection and selective protection of the phenolgroup to yield derivative (94). Derivative (94) is reacted withp-CN-phenol to yield compound (95), and followed by addition ofLi-derivative (75) and then dehydration (as described in Example 8), toyield compound (96). Subsequent deprotection yields compound LII aspresented in FIG. 5.

Example 13 General Synthesis of Compound XXIV (FIG. 1I)

4-(4-Arylsulfonyl-2,5-dimethyl-piperazin-1-yl)-2-trifluoromethyl-benzonitrilewere prepared according to FIG. 1I. Nucleophilic substitution offluorine atom in 4-fluoro-2-trifluoromethyl benzonitrile with2,5-dimethyl-piperazine was carried out in a presence of potassiumcarbonate in DMSO-water mixture. Corresponding arylsulfonyl derivativeswere prepared by reaction with arylsulfonyl chlorides in a presence oftriethylamine.

Example 14 Androgen Receptor (AR) Binding of SARMs and AR-SARM CrystalStructure Methods Binding Affinity Determination

Cytosolic AR was obtained from ventral prostates of Sprague-Dawley rats.Prostates were excised and immediately immersed in ice-coldhomogenization buffer (10 mM Tris, 1.5 mM disodium EDTA, 0.25 M sucrose,10 mM sodium molybdate, and 1 mM PMSF). Prostates were minced withscissors, homogenized, and centrifuged (Model L8-M, Beckman InstrumentsInc). The supernatant (cytosol) was collected and stored at −80° C.until use. Aliquots (50 μL) of AR cytosol were incubated with asaturating concentration of ³H-MIB (1 nM) and 1 μM of triamcinoloneacetonide at 4° C. for 18 hours in the absence or presence of increasingconcentrations of the compound of interest (10˜¹ nM to 10⁴ nM).

Nonspecific binding of ³H-MIB was determined by adding 1000 nM MIB tothe incubate. Bound and free radioligand was separated usinghydroxyapatite and the concentration of bound ³H-MIB was determined. TheIC₅₀, the concentration of the test compound that inhibited the specificbinding of ³H-MIB by 50%, is determined using nonlinear regression.

Binding affinities of compounds of this invention were determined andpresented in the following Table:

compounds Ki (nM)

633.5

528.9 nM

195.81 nM

412.24 nM

396.8 nM

micromolar range

micromolar range

70.7 nM

2785 nM

2632 nM

Cotransfection Assay

CV-1 cells (green monkey kidney cells) were grown in Dulbecco's modifiedEagles's medium (DMEM) supplemented with 10% FBS, 2 mM glutamine and 1%streptomycin and penicillin to confluency in T175 tissue culture flasks.Cells were transfected with 3 pg of the CMVhAR expression vector, 30 μgof an androgen-dependent luciferase reporter construct (pMMTV-luc) and30 μg of a galactosidase expression construct (pSV-β-galactosidase;Promega, 5 Madison, Wis.) via 30 mL Plus reagent (Invitrogen) and 40 mLLipofectAMINE (Invitrogen) in serum-free DMEM. After 4 hours, the mediumis exchanged to DMEM supplemented with 0.2% FBS and 2 mM glutamine.Cells were transferred 12 hours later to 24-well tissue culture platesand after another 6 hours are treated with 0.1 nM to 1000 nM, or no drug(control). After another 24 hours, cells are washed twice with cold PBSand are harvested by incubation with 100 mL of passive lysis buffer(Promega) for 30 minutes.

An aliquot (50 mL) of the lysate was added to an opaque 96-well plateand luciferase activity was monitored after automated injection of 50 mLof luciferase substrate (Promega) with a MicroLumatPlus LB96Vluminometer (Berthold Technologies, Oak Ridge, Tenn.) using the WinGlowsoftware package. An aliquot (50 mL) of the lystate also was added to aclear 96-well plate along with 50 mL of β-galactosidase assay buffer. Anabsorbance measurement at 420 nM was taken following a two hourincubation at 37° C. on a Dynex MRX plate reader. Luciferase activitywas normalized with β-galactosidase activity to account for differencesin cell number and/or loss in transfection efficiency.

Cloning, Expression and Purification

An AR-LBD (663-919) was obtained by PCR amplification from a full-lengthAR expression construct (pCMVhAR) with primers containing flankingrestriction sites and was inserted into the pGEX6P-1 plasm id vector(Amersham). The AR LBD was expressed as a glutathione-5-transferase(GST) fusion protein in E. coli BL21 DE3 at 15° C. for 16 hours byinduction with 30 μM IPTG. Cells were lysed in a buffer containing 150mM NaCl, 50 mM Tris pH 8.0, 5 mM EDTA, 10% glycerol, 1 mg/mL lysozyme,10 U/mL DNase I, 10 mM MgCl₂, 10 mM DTT, 0.5% CHAPS, 100 μM ligand and100 μM PMSF by 3 cycles of freeze-thaw. The supernatant fromultracentrifugation was incubated for 1 hour at 4° C. with glutathionesepharose (Amersham) and washed with 150 mM NaCl, 50 mM Tris pH 8.0, 5mM EDTA, 10% glycerol, 10 mM ATP, 10 DM ligand, 0.1%n-octyl-β-glucoside, and 1 mM DTT.

The GST-LBD fusion protein was cleaved in a buffer containing 150 mMNaCl, 50 mM Tris pH 7:0, 10% glycerol, 10 μM ligand, 0.1%n-octyl-β-glucoside, 1 mM DTT, and 5 U/mg protein PreScission protease(Amersham) at 4° C. overnight to release the AR LBD from the glutathionesepharose resin. The supernatant was diluted 3-fold in 10 mM Hepes pH7.2, 10% glycerol, 10 μM ligand, 0.1% n-octyl-β-glucoside, and 1 mM DTTand was loaded onto an HP SP cation exchange-column (Amersham). Proteinwas eluted with a gradient of 50 mM to 500 mM NaCl in the same dilutionbuffer. The buffer was exchanged in a Millipore 10 kD cut-offconcentrator to a buffer containing 150 mM Li₂SO₄, 50 mM Hepes pH 7.2,10% glycerol, 100 μM ligand, 0.1% n-octyl-p-glucoside, and 10 mM DTT andprotein was concentrated to above 4 mg/mL.

Crystallization, data collection and structure determination AR LBDcrystals were formed in one to two days using the hanging drop vapordiffusion method in 0.1 M Hepes pH 7.5 and 0.5 M to 0.8 M sodiumcitrate. Prior to flash freezing in liquid nitrogen, AR LBD crystalswere transferred to a solution consisting of 0.1 M Hepes pH 7.5, 0.7 Msodium citrate, and 20% ethylene glycol. Diffraction data are collectedusing a Rigaku RU300 rotating anode generator and an R-axis IV++ imageplate (Rigaku) and were processed with Crystal Clear software (MolecularStructure Corporation). The AR LBD-DHT complex (PDB code 1I37) was usedas a starting structure for refinement using Crystallography & NMRSystem (CNS). After an initial round of refinement, electron densitymaps allow for accurate fitting of the ligand. Model building and watermolecules were added using the program O and further rounds ofrefinement were performed using rigid body, torsion angle simulatedannealing and individual temperature factor modules of CNS.

X-Ray Studies of SARMs

SARMS showing AR binding at below the 100 nM level were further analyzedin a luciferase assay to determine if they possessed AR functionalagonist activity. SARMs with the highest activity subsequently arecocrystallized with the AR receptor and X-ray analysis was performed.

Example 15 Functional Activity of SARMs

Table 1 describes the structure and binding affinity of the indicatedether-linked compounds that are analogs of bicalutamide. All compoundswere synthesized using a chiral synthetic method involving the use ofD-proline as a chiral auxiliary as disclosed in U.S. Pat. No. 6,995,284which is incorporated herein by reference. The structures of thesynthesized compounds were confirmed using elemental analyses andspectroscopic data, i.e., ¹H NMR, ¹³C NMR, MS, and IRE.

In some aspects of this invention, design of the compounds appreciatesthe structural elements identified as being involved in the AR bindingaffinity of bicalutamide analogs, such as: (i) an electron-deficientaromatic A-ring, (ii) an R-configuration at the chiral center, and (iii)an electrophilic group at the para-position of the B-ring. It isimportant to note that the chiral designation for active compoundschanges from (R) to (S) when replacing the thioether or sulfonyl linkagewith the ether linkage in this class of molecules. Besides thesestructural features required for high affinity AR binding, B-ringsubstitution and the nature of the linkage group X are criticaldeterminants of the functional activity for bicalutamide analogs.

TABLE 1

No. R1 R2 X R3 R4 R5 R6 R7 Ki (nM) Bical CN CF₃ SO₂ H H F H H 11 ± 2 R-20 NO₂ CF₃ SO₂ H H COCH3 H H 9.3 ± 0.8 S-1 NO₂ CF₃ O H H F H H  6.1 ±0.19 S-2 NO₂ CF₃ O H H COCH3 H H 36.6 ± 2.3  S-3 NO₂ CF₃ O H H COCH₂CH₃H H  6.1 ± 0.14 S-4 NO₂ CF₃ O H H NHCOCH3 H H  4.0 ± 0.70 S-5 NO₂ CF₃ OH H CH₃ H H 34.8 ± 3.5  S-6 NO₂ CF₃ O H H OCH3 H H 13.7 ± 0.68 S-7 NO₂CF₃ O H H NHCO₂C(CH₃)3 H H 336.0 ± 71.1  S-9 NO₂ CF₃ O H H H H H  4.6 ±0.26 S-10 NO₂ CF₃ O F H F H H  3.4 ± 0.34 S-11 NO₂ CF₃ O H F F H H  3.4± 0.56 S-12 NO₂ CF₃ O F H F H H  3.2 ± 0.30 S-13 NO₂ CF₃ O CH3 H F H H 6.0 ± 0.70 S-14 NO₂ CF₃ O H Cl F H H 10.3 ± 2.0  S-15 NO₂ CF₃ O H F ClH H 4.9 ± 0.3 S-16 NO₂ CF₃ O H Cl Cl H H  1.0 ± 0.088 S-17 NO₂ CF₃ O F FF H H 11.3 ± 1.1  S-18 NO₂ CF₃ O F H F H F 10.3 ± 2.0  S-19 NO₂ CF₃ O FF H F H 9.1 ± 0.6 S-20 NO₂ CF₃ O F F F F F  1.4 ± 0.34 S-21 NO₂ CF₃ O HH Cl H H 8.6 ± 1.2 S-22 NO₂ CF₃ O H H Br H H 12.6 ± 1.8  S-23 NO₂ CF₃ OH H I H H 22.6 ± 1.6  S-24 NO₂ CF₃ O H H NHCSNH₂ H H 10.2 ± 1.4  S-25NO₂ CF₃ O H H NHCSNHCH₃ H H 271.2 ± 37.2  S-26 CN I O H H F H H  3.3 ±0.10 S-27 CN CF₃ O H H Cl H H  3.4 ± 0.08 S-28 CN CF₃ O H H NHCOCH₃ H H12.7 ± 0.02 S-29 CN Cl O H H F H H  4.5 ± 0.11 S-30 CN CF₃ O H H F H H 3.3 ± 0.08 S-31 F CF₃ O H H F H H 32.6 ± 0.10 S-32 Cl CF₃ O H H F H H14.5 ± 0.18 S-33 I CF₃ O H H F H H 15.6 ± 0.19 S-34 Br CF₃ O H H Cl H H52.0 ± 0.13 S-35 Br CF₃ O H H Br H H 25.9 ± 0.04 S-36 H CF₃ O H H F H H62.0 ± 0.05

In vitro studies of AR-mediated transcriptional activation (FIG. 8)showed that either changing the X-linkage from sulfone to an oxygen orchanging the B-ring para-position substitution from fluorine to anacetamide group converted a pure AR antagonist into an agonist, forexample, as in compounds S-5 and R-20. During in vivo testing, leadcompounds S-1 and S-4 functioned as AR agonists in vivo and demonstratedtissue selectivity (FIGS. 9A-9B). Both S-1 and S-4 are partial agonistsin the prostate, but full agonists in the levator ani muscle, bone, andpituitary, which are features proposed for an ideal selective androgenreceptor modulator.

The oral bioavailability and safety profile of S-4 has been demonstrated(data not shown), corroborating the idea that these compounds may beefficacious for treating androgen-deficient diseases or disorders. Ithas been demonstrated previously that S-1 and S-4 are not substrates for5α-reductase. It is contemplated that the tissue selectivity of theseligands is because their agonist activity in the prostate is not fullyamplified by 5a-reductase, an enzyme expressed in the prostate but notin the muscle that converts testosterone to DHT.

Table 2 demonstrates the dependence of percent maximum efficacy on theX- and Y-positions of various compounds of Table 1. Intact AR bindingaffinities were determined using a competitive binding assay using ratventral cytosol as the source for AR described in Example 13. Intact ARin vitro functional activity was examined using a cotransfection assayas described in Example 13. Efficacy, i.e., transcriptional activation,was assayed at 10 nM of ligand and activity was expressed as a % maximumtranscriptional activation observed for 1 nM dihydrotestosterone (DHT).

TABLE 2

Affinity Efficacy ID X Y (nM) (% max) S-1 O F 6.11 ± 0.19 43.40 ± 2.60X-2 S F 11 ± 2  77.4 ± 5.6 X-3 SO₂ F 28 ± 10 18.8 ± 9.3 X-4 NH F 7.96 ±0.43 21.33 ± 2.22 X-5 CH₂ F   9 ± 0.2 28.9 ± 2.4 S-4 O NH(CO)CH₃ 3.98 ±0.70 92.92 ± 7.00 S-23 O I  23 ± 1.6 47.2 ± 1.8

Example 16 Structural Characterization of Nonsteroidal Ligand Binding

A conformational analysis of a series of4″-fluorophenyl-2-hydroxy-2-methyl-N-(4′-nitro-3′-trifluoromethylphenyl)propionanilide compounds that differed only at the X-position heteroatomwas performed. This analysis examined the effects of X-positionsubstituents on compound conformations in solution to develop aconformational compound. The ligand solution (DMSO-d₆) NMR conformationswere compared to their bound conformations from the recently solvedR-bicalutamide-W741L-LBD crystal structure (referred herein asbical-W741L; C. E. Bohl, W. Gao, D. D. Miller, C. E. Bell, J. T. Dalton.Structural basis for antagonism and resistance of bicalutamide inprostate cancer. Proc Natl Acad Sci USA 2005, 102(17), 6201-6.). Anintramolecular hydrogen bonding (NH to OH) in the linker that was seenin the solution conformations has been predicted. However, thisintramolecular NH hydrogen bond donation was shared between the OH andthe X-position for some of the compounds analyzed. The NH—X hydrogenbond caused the gross shape of the ligands in solution to acquire anunexpected bend that differed significantly from the hypothetical boundconformation derived during homology modeling of AR. The six-membered 5annular NH to X hydrogen bonding configuration was not previouslypostulated for propionanilides. This NH to —X plus —OH conformation ofthe phenyl rings in solution (FIG. 10) was most clearly exhibited by theagonists S-4 (X═O, Y═N-acetyl) and X-2 (X═S, Y═F) and the partialagonist S-23 (X=0, Y═I) and S-1 (X=0, Y═F) and not observed for theantagonists of the series, X-3 (X═SO₂, Y═F) and X-4 (X═NH, Y═F) and X-5(X═CH₂,Y═F). This suggests that the ability of the ligand to adopt thisconformation may be important for activation of the AR, as corroboratedby comparison to the nonsteroidal ligand conformation observed in thesubsequently solved X-ray crystal structure of R-bicalutamide-W741L-LBD,an AR mutant in which bicalutamide acts as an agonist.

Table 3 gives the results of an intramolecular hydrogen bonding analysisin solution of various compounds identified in Table 1. The definitionof a hydrogen bond, as used in Table 3, is an interatomic distance of<3.1 Å with distances measured in SYBYL 6.8 using the Analysis ->>Distances command.

The solution conformation was determined using NOESY spectroscopy. NH—OHrefers to the interatomic distance between the linker amide proton andthe linker hydroxyloxygen and NH—X refers to the interatomic distancebetween the linker amide proton and the linker X-position atom. S-1 actsas a partial agonist in vitro, S-4 and X-2 are agonists in vitro andX-3, X-4 and X-5 are antagonists in vitro.

TABLE 3 ID NH—OH NH—X S-1 2.4 2.3 S-4 2.7 1.9 X-2 2.1 3.0 X-3 2.0 3.6X-4 2.3 4.4 X-5 2.0 3.9

Site-specific mutants of the AR were constructed and the ability of DHTand three nonsteroidal ligands, i.e., hydroxyflutamide (HF),bicalutamide, and S-4, to stimulate AR-mediated transcription wereexamined (FIG. 11). In this mutant, bicalutamide behaves as an agonistand stimulates AR-mediated transcriptional activation, suggesting thatbicalutamide bound W741L mutant AR-LBD adopts the active conformationsimilar to that observed with agonist-bound wt-AR. Considering thedifficulty in purifying antagonist-bound wt-LBD, the agonistconformation of bicalutamide-bound W741L mutant andhydroxyflutamide-bound T877A mutant proved useful. It was contemplatedthat these mutant complexes would adopt the more compact conformation,which would facilitate the dissociation of the chaperone proteins duringpurification and crystallization of LBD and provide us the first viewtoward the binding mechanism of nonsteroidal AR ligands.

Using methods similar to that described by those that first solved theAR-LBD crystal structures bound to the steroidal ligands, R1881 and DHT,DHT-5 bound wt-LBD and bicalutamide-bound W741L LBD were purified andcrystallized. Further, the higher binding affinity R-isomer ofbicalutamide was used. GST-LBD was coexpressed with ligand in E. coli.Following affinity chromatography and cleavage of the fusion protein,the high pI (isoelectric point) of LBD allows for removal ofcontaminating and chaperone proteins by cation-exchange chromatographyat neutral pH.

Both complexes adopt very similar overall conformation (FIG. 12A) as thesteroid-bound LBD. As predicted by NMR studies of solution conformation,bicalutamide forms an intramolecular hydrogen bond between the sulfonyloxygen and the amine proton (FIG. 12B) that is different fromcomputer-predicted models (FIG. 10), indicating a different conformationthat ether-linked analogs and suggesting that NMR studies of thesolution conformation of ligands may be useful for prediction of ligandconformation when bound to the LBD. The structures demonstrate thatthese mutations accommodate more space for the nonsteroidal ligand tofit into the LBD and result in an agonist conformation seen with thewt-DHT complex.

Most LBD residues are positioned similarly in the wt-DHT complex ascompared to the nonsteroidal complexes despite the striking degree ofvariation in ligand structures (FIG. 13A). Hydroxyflutamide (HF) andR-bicalutamide share similar A-ring and amide bond structure, whichperfectly overlaps the steroidal plane (FIG. 13B). Hydrogen bonds wereobserved between R752 and the A-ring nitro/cyano group, which mimics the3-keto group in DHT, and between L704 and N₇O₅ and the hydroxyl group,which mimics the 17β-OH group in DHT. However, different from DHT, nohydrogen bond was observed between the nonsteroidal ligands and the T877side chain.

Considerable differences in residue positions are also noticed in theregion of the R-bicalutamide sulfone linkage group and the B-ring (FIG.13B), which folds away from the steroidal plane and points to the top ofthe pocket, possibly taking the space for the W741 indole ring (notpresent in the mutant). The location of the W741 indole ring alsodiffers significantly between the T877A-HF and WT-DHT complexes. In theDHT-complex, the Trp741 side-chain contacts the ligand, while in theT877A-HF complex, the indole ring is more distant from the bindingpocket. Displacement of M745 by the 19-methyl group of DHT seems toaccount for these differences. Also seen in FIG. 13B is that theR-bicalutamide sulfonyl group causes displacement of the helix 12residue, M895, as compared to the WT-DHT and T877A-HF complexes. ThisM895 side-chain is however accommodated in the location of the W741indole ring of T877A-HF complex. In wt-LBD, both W741 and M895 sidechains could have unfavorable interactions with bicalutamide, whichcould prevent the formation of the agonist conformation. On the otherhand, the fluorine on the para-position of the B-ring of R-bicalutamidebinds in a hydrophilic region of the AR that also offers hydrogen bondopportunities. This area of the AR is at the turn between helices 4 and5, and is closely bordered by the H874 imidazole. The compoundssubstituted with an acetamido S-4, isothiocyanate, cyano, or nitro groupat this position demonstrate improved binding affinity to the AR,indicating that they might form a favorable hydrogen bond in thisregion.

Example 17 Structural Features of Agonist and Antagonist Bound AR LBD

The dissociation of HSP is one of the first processes initiated by theagonist-induced conformational change in AR LBD. In mammalian cells, theHSP complex mainly contains HSP90, HSP70, p60 and p23. HSP90 directlybinds to the receptor as homodimer, while other proteins mainly bind tothe complex through HSP90. The HSP90 binding site in AR LBD has not beenwell characterized. Residues 720-774, which includes loop 3-4, H4 andH5, which happen to form a large portion of the AF2 hydrophobic groove(FIGS. 14A-14B) were identified as the region that might be responsiblefor HSP90 binding using truncated.

Importantly, it is contemplated that an unusual solvent-exposed a-helixof HSP90 is remarkably similar to H12 of the nuclear receptor family,and may displace H12 on these receptors to facilitate ligand binding.This observation may be particularly relevant to the AR, as there appearto be important differences in AR function as compared to other nuclearreceptors. IP and sucrose gradient centrifugation analyses of theradiolabeled AR showed that agonist R1881, but not antagonistshydroxyflutamide and bicalutamide, induce HSP90 dissociation, suggestingthat the presence of the chaperone protein complex and not the MAEIImotif of H12 blocks access to the AF2 region. Thus, the dissociation ofHSP90 appears to be directly related to the activity of AR ligands.

Although hydroxyflutamide functions as an antagonist for wt-AR, it actsan agonist with the T877A AR mutant. Its agonist activity in the mutantAR is directly related to dissociation of HSP90. This is completelydifferent from the ER where both ER agonists and antagonists initiateHSP90 dissociation. The association of HSP90 to AR LBD appears to be amore critical factor that can affect the conformation of the receptorthan is the case in ER. This suggests that an alternative mechanismmight be involved in AR antagonist activity.

Limited proteolysis analyses of different AR complexes suggests that twosequential conformational changes of the LBD are required for theligand-induced activation of AR. AR agonists, i.e., T, DHT and R1881,stabilized a 29-KDa fragment of the AR against limited trypsinization,while antiandrogens, i.e., cyproterone acetate, hydroxyflutamide,nilutamide and bicalutamide, stabilized a 35-KDa fragment. Both the29-KDa and the 35-KDa fragments contain the whole LBD (amino acids671-919), and the 35-KDa fragment extended into the hinge region (aminoacids 621-671). The 35-KDa fragments are also involved in the initialstep of agonist binding, but are not stable under prolonged digestion.

This time-dependent conformational change was delayed by the addition ofmolybdate, which indicates that the dissociation of HSP might result inthe exposure of the hinge region to trypsinization. Therefore, it hasbeen proposed that agonist binding initiated the first conformationalchange in AR, which triggered the dissociation of HSPs and then startedthe second conformational change. However, although an antagonist caninitiate the first conformational change, it was unable to promotedissociation of HSPs, which stabilized both LBD and the hinge region andprotected it from further trypsin digestion.

Example 18 De Novo Approaches to Structure Based Drug Design (SBDD) ofSARMs

The AR mutant W741L bound to the antagonist bicalutamide (bicW741L)provided insight into the binding mode of the compounds provided hereinin terms of design of agonists based on their binding conformation tothe AR. It also provided a rationale for the distinguishing binding modefeatures between agonist and antagonist. The recently solved crystalstructure of the wildtype AR bound to the agonist S-1 (SI-wt) confirmedthe binding mode observed in the W741L mutant. These structures wereboth solved at 1.8 Å resolution and demonstrated a novel binding modethat is radically different from that suggested by a homology model thatwas proposed prior to the cocrystals structure.

Contrary to the cocrystal above, the homology model possessed a uniqueunoccupied cavity along the α-face of the docked steroid large enough tocontain the B-ring of the propionanilides.

Validation of De Novo SBDD Models

Empirical analysis of these AR structural models via Spearmancorrelation coefficient analysis provided a statistical measure of theability of each model to predict rank order of ligand affinities. Thisrank order statistic is 5 appropriate when using a molecular dockingbased approaches such as de novo design or virtual screening to evaluatewhether the model can be used to prioritize which in silico leads shouldbe pursued. The database of AR ligands that was compiled for acomparative molecular field analysis (CoMFA) model was used in theSpearman analysis of the following AR models: CoMFA, S-1 bound wildtypecrystal (abbreviated as S1-wt), bicalutamide-bound W741L crystal(abbreviated as bic-W741L), and homology. The R_(s) values for the CoMFA(C. E. Bohl, C. Chang, M. L. Mohler, J. Chen, D. D. Miller, P. W. Swaan,J. T. Dalton. A ligand-based approach to identify quantitativestructure-activity relationships for the androgen receptor. J Med Chem2004, 47(15), 3765-76.)), S1-wt (C. E. Bohl, D. D. Miller, J. Chen, C.E. Bell, J. T. Dalton. Structural basis for accommodation ofnonsteroidal ligands in the androgen receptor. J Biol Chem 2005,280(45), 37747-54.), bic-W741L (C. E. Bohl, W. Gao, D. D. Miller, C. E.Bell, J. T. Dalton. Structural basis for antagonism and resistance ofbicalutamide in prostate cancer. Proc Natl Acad Sci USA 2005, 102(17),6201-6.), and G1 homology models ((C. A. Marhefka, B. M. Moore, 2nd, T.C. Bishop, L. Kirkovsky, A. Mukherjee, J. T. Dalton, D. D. Miller.Homology modeling using multiple molecular dynamics simulations anddocking studies of the human androgen receptor ligand binding domainbound to testosterone and nonsteroidal ligands. J Med Chem 2001, 44(11),1729-40.)) were 0.93, 0.55, 0.29, and −0.28 respectively, indicatingsignificant predictive value for the S1-wt model and limited predictivevalue for the bic-W741L model and represent an improvement compared withprevious structure based drug design models. Therefore these crystalstructures can be expected to improve the ability to prioritize insilico leads thereby accelerating drug design.

Example 19 Confirmation of Computational Predictions for AR LigandBinding

Examination of torsional strain parameters and hydrogen bondinginteractions as in Example 16 revealed that the aryl propionamidederived compounds of compound XVII adopt a conformation similar to thatof compound XLII. The hydroxyl group a to the carbonyl undergoespositioning in such a manner that it enters into hydrogen bondinginteraction with Aspargine705 of the receptor. The amino group forms aweak hydrogen bond with the back bone oxygen of Leucine 704. Thecomputational predictions made were in agreement with the resultsobtained from the binding assays. However to convincingly establish theaforesaid interactions and the conformation adopted by the molecules, asuitable molecular model which did not have free hydroxyl and amideprotons and which, above all, was conformationally restricted to astructure similar to compound XLII. Thus, the amide nitrogen and thehydroxyl oxygen were interlocked by a carbonyl functionality which ledto the oxazolidinedione derivative structure depicted in compound XXXIX.Synthesis of the aryl propionamide-derived compounds and stereoselectivesynthesis of these oxazolidinedione derivatives were performed.

Example 20 Synthesis of Compound LIV

Compound LIV is synthesized via the The initial set of compoundsconsidered were a series of cyclopropanes that would be synthesized viathe Simmons-Smith reaction compound LII, as illustrated in scheme below.

Example 21 Synthesis of Compound XVI

Compound XVI was synthesized according to the above scheme R-3 wassynthesized according to U.S. Pat. No. 6,995,284, which is incorporatedhere by reference. XVI was obtained as a yellowish oil: Calculated Mass415.08, [M-H] 414.0; ¹H NMR (CDCl₃) 9.13 (bs, 1H, NH), 7.96 (d, J=9.0Hz, 2H, ArH), 7.88 (dd, J=9.0, 2.1 Hz, 1H, ArH), 7.43 (dd, J=7.6, 1.5Hz, 1H, ArH), 7.11 (m, 1H, ArH), 6.72 (m, 2H, ArH), 4.15 (bs, 3H, OH &NH2), 3.59 (d, J=14.1 Hz, 1H, CH2), 3.02 (d, J=14.1 Hz, 1H, CH2), 1.56(s, 3H, CH3).

Example 22 Synthesis of Compound XL

Compound XL was synthesized as depicted in FIG. 1J. To a sodium salt ofL-alanine in ethanol was added phenylisothiocyanate and warmed for 30min. The solvent was evaporated and to the oily residue was addedconcentrated HCl. The white solid formed was collected, washed in H₂O,to obtain compound 2. Acetic anhydride was added to obtain compound3,1-Bromo-4-bromomethyl-benzene was added in the presence ofpotassium-hexamethyldisilazane to yield compound XL.

¹H NMR (CDCl₃) of compound 2: 7.65, 7.63, 7.61, 7.38, 7.35, 7.25, 4.40,1.62

¹H NMR (CDCl₃) of compound 3: 7.59, 7.57, 7.56, 7.39, 7.33, 4.92, 2.90,1.74

¹H NMR (CDCl₃) of compound XL: 7.53, 7.52, 7.51, 7.50, 7.49, 7.40, 7.39,7.37, 7.34, 4,38, 1.67, 1.66; m.p of compound XL: 99° C.

Example 23 Synthesis of Compound XLI

Compound XLI was synthesized as depicted in FIG. 1K. To a sodium salt ofL-alanine in ethanol was added4-Isothiocyanato-1-nitro-2-trifluoromethyl-benzene and warmed for 30min. The solvent was evaporated and to the oily residue was addedconcentrated HCl. The white solid formed was collected, washed in H₂O,to obtain compound 2. Acetic anhydride was added to obtain compound3,1-Bromo-4-bromomethyl-benzene was added in the presence ofpotassium-hexamethyldisilazane to yield compound XLI.

¹H NMR (CDCl₃) of compound 3: 10.80, 8.35, 8.18, 7.99, 4.49, 1.43.

¹H NMR (CDCl₃) of compound XLI: 7.97, 7.47, 7.43, 7.42, 7.19, 7.15,6.97, 6.92, 3.93, 3.15, 2.88, 1.98.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

1. A compound represented by the structure of formula I:

wherein X is C or N; W is C or N; X₁ is N, NH, N(C₁₋₄alkyl), NAc, NCOOH,or a bond; or X₁ and X₃ together with X₂ and X₅ to which X₁ and X₃ areattached, form a saturated or unsaturated, substituted or unsubstituted5- or 6-membered ring; or X₁ and X₅ together with X₂ to which X₁ and X₅are attached form a saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring and A is nothing; P is H or formulaII:

X₂ is C₁₋₄alkylne, SO₂, C(O), CH—[CH₂—C₄₋₈ring)], CH(C₁₋₄ alkyl),CH(NH₂), CH(OH), CH(C₁₋₄haloalkyl), a bond; or X₂ and R₃ together withX₁, to which X₂ is attached, form a ring, which is a saturated orunsaturated, substituted or unsubstituted 5 or 6 membered ring; or X₂and X₅ form a saturated or unsaturated, substituted or unsubstituted 5-or 6-membered ring and A is nothing, X₃ is Cl₁₋₄alkylene, NH, N, CH(OH),a bond, or X₃ and X₁ together with X₂ and X₅ to which X₁ and X₃ areattached form a saturated or unsaturated, substituted or unsubstituted5- or 6-membered ring; or X₃ and X₅ form a saturated or unsaturated,substituted or unsubstituted 5- or 6-membered ring and A is nothing; orX₃ and X₄ form together a double bond or form together a saturated orunsaturated, substituted or unsubstituted 3 to 6 membered ring. X₄ is O,S, SO, C(O), S(O)[═CHCH₂N(CH₃)]₃ SO₂, NH, NHR′, NO, C₁₋₄alkylene,C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂],NO[CH₂CH₂N(CH₃)₂] or a bond; or X₄ and X₅ together with X₃, to which X₄and X₅ are attached form a saturated or unsaturated membered,substituted or unsubstituted 5- or 6-membered ring and A is nothing; orX₃ and X₄ form together a double bond or form together a saturated orunsaturated, substituted or unsubstituted 3 to 6 membered ring. X₅ is acarbon or X₅ and X₁ together with X₂ to which X₁ and X₅ are attachedform a saturated or unsaturated, substituted or unsubstituted 5- or6-membered ring and A is nothing; or X₃ and X₂ form a saturated orunsaturated, substituted or unsubstituted 5- or 6-membered ring and A isnothing; or X₅ and 3 form a saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring and A is nothing; or X₅ and X₄together with X₃, to which X₅ and X₄ are attached form a saturated orunsaturated, substituted or unsubstituted 5- or 6-membered ring and A isnothing, A is nothing, H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN,CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂CF₃,CF₂CF₃, CH₂OR′CH₂C(O)CH₇═CH₂ or C(O)CH═CH₂; or A with R forms a doublebond represented by formula III:

Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; Y is H,C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br; Q is H, CN, OH, NO₂, halide,CF, C₂₋₆alkenyl, C₂₋₆-alkynyl, C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl),C(O)N(C₁₋₄alkyl), C(O)NH₂, NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl),CH₂C(O)NH₂, NHC(O)NH₂, NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl),O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₁₋₄-cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(CH₃)₂]; R is H, OH,C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl); R₁ is H, OH, NH₂, F,Cl, Br or I; R₂ is H, benzyl substituted with R₆,(CH₂)₂—O-p-cyanophenyl, CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl;R₃ is H, C₁₋₄alkyl, halide, CN, NO₂; or R₃ and X₂ together with thebenzene ring to which R₃ is attached and X₁ to which X₂ is attached forma ring, which is a saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring; R′ is NH₂, OH or CH₃; R₄ and R₅ areindependently H, CH₃, halide, OH, C₁₋₄alkyl, C₁₋₆cycloalkyl,halo(C₁₋₄alkyl), phenyl, aryl, C₄₋₈heterocycloalkyl, orhydroxy(C₁₋₄alkyl); R₆ is CN, NO₂, NHC(O)CH₃ or halide; wherein if P isformula II, X is C, X₁ is NH, X₂ is C(O), X₃ is CH₂, R is OH and A isalkyl or haloalkyl, then X₄ is S(O)[═CHCH₂N(CH₃)₂],C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂], N[CH₂CH₂N(CH₃)₂],P(O)(C₁₋₄alkyl) or N(O)[CH₂CH₂N(CH₃)₂]; or if P is formula II, X is C,X₁ is NH, X₂ is C(O), X₃ is CH₂, R is OH or OAlk and X₄ is O, S, NH, S,SO, SO₂ or alkylene, then A is CN, CH₂OH, CH₂O(C₁₋₄alkyl),CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, C₁₋₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′,C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂OR′CH₂C(O)CH═CH₂ orC(O)CH—CH₂; or if P is phenyl, X is C, X₁ is NH, X₂ is C(O), R is OH andA is COOH, X₃ is a bond, X₄ is CH₂, R₁, R₂ are H then Q is not H, or ifP is formula II, X is C, X₃ is CH₂, X₄ is O, or NH, R₁, R₂ and R₃ are H,and X₅ and X₁ forms a 5 membered ring, an oxazolidine-2-one then Q isnot halogen, or H; or if P is H, X is C, X₁ is NH, X₂ is C(O), R is OH,A is alkyl, X₃ is a bond or CH₂ and X₄ is bond or CH₂, R₁ and R₂ are H,then Q is not H or halogen.
 2. The compound of claim 1, represented bythe following structure:


3. The compound of claim 1, wherein said compound is represented by thestructure of formula IV:

wherein X is Cor N; W is C or N; X₂ is C₁₋₄alkylene, SO₂,CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄ alkyl), CH(NH₂), CH(OH), CH(C₁₋₄haloalkyl),a bond; X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl),N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a bond; A is H, OH, SH, NH₂,C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl),CH₂CN, CH₂N₃, CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,C(O)O(C₁₋₄alkyl), C(O)R′, CH₂CF₃, CF₂CF₃ CH₂OR′CH₂C(O)CH═CH₂ orC(O)CH═CH₁₂; Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; Y isH C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I or Br; Q is H, CN, OH, NO₂, CF₃,halide, C₂₋₆alkenyl, C₂₋₄alkynyl, C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl),C(O)N(C₁₋₄alkyl)₂, C(O)NH₂, NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl),CH₂C(O)NH₂, NHC(O)NH₂, NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl),O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₄₋₈cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(CH₃)₂]; R is H, OH,C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) or O(C₁₋₄acyl); R₁ is H, OH F, Cl Bror I; R₂ is H benzyl substituted with R₆ (CH₂)₂—O-p-cyanophenylCH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl; R₃ is H C₁₋₄₄alkyl,halide, CN or NO₂; R′ is NH₂, OH or CH₃; and R₆ is CN, NO₂, NHC(O)CH₃ orhalide.
 4. The compound of claim 3, represented by the followingstructure:


5. The compound of claim 2, wherein said compound is represented by thestructure of formula V:


6. The compound of claim 5, represented by the following structure:


7. The compound of claim 2, wherein said compound is represented by thestructure of formula VI:

wherein X is C or N; W is C or N X₄ is O, S, SO, C(O),S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO, C₁₋₄alkylene,C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂],NO[CH₂CH₂N(CH₃)₂] or a bond; A is H, OH, SH, NH₂, C₁₋₄alkyl, CHF₂, CH₂F,CF₃, CN, CH₂OH, CH₂O(C₁₋₄alkyl), Cl₂O(C₁₋₄acyl), CH₂CN, CH₂N₃ CH₂NCS,CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′,CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH—CH₂; Z is H, CN, NO₂,NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; Y is H, C₁₋₄alkyl, CF₃, CN, NO₂,F, Cl, I or Br; Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl,C₂₋₆alkenyl, C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂C₁₋₂CH(CH₃)₂],O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] orO—[CH₂CH₂N(CH₃)₂]; R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) orO(C₁₋₄acyl); R₁ is H, OH, F, Cl, Br or I; R₂ is H, benzyl substitutedwith R₆, (CH₂)₂—O-p-cyanophenyl, CH₂—O-p-cyanophenyl, orCH═CH₄₀-p-cyanophenyl; R₃ is H, C₁₋₄alkyl, halide, CN or NO₂; R′ is NH₂,OH or CH₃; and R₆ is CN, NO₂, NHC(O)CH₃ or halide.
 8. The compound ofclaim 7, represented by the following structure:


9. The compound of claim 7, wherein said compound is represented by thestructure of formula VII:


10. The compound of claim 9, represented by the following structure:


11. The compound of claim 9, wherein said compound is represented by thestructure of formula VIII:


12. The compound of claim 11, represented by the following structure:


13. The compound of claim 7, wherein said compound is represented by thestructure of formula IX:


14. The compound of claim 13, represented by the following structure:


15. The compound of claim 7, wherein said compound is represented by thestructure of formula X:


16. The compound of claim 7, wherein said compound is represented by thestructure of formula XI:


17. The compound of claim 16, represented by the following structure:


18. The compound of claim 17, wherein A is CH₂OH or CH₂OMe. 19.(canceled)
 20. The compound of claim 17, wherein A is CF₃, CH₃ or CN.21. (canceled)
 22. (canceled)
 23. The compound of claim 1, wherein saidcompound is represented by the structure of formula XII:

wherein X is C or N; W is C or N; X₄ is O, S, SO, S(O)[═CHCH₂N(CH₃)₂],SO₂, NH, NHR′, NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂] or a bond; A is CN,CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl), CH₂CN, CH₂N₃, CH₂NCS, CHO,C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂, C(O)O(C₁₋₄ alkyl), C(O)R′,CH₂OR′CH₂C(O)CH═CH₂ or C(O)CH═CH₂; Z is H, CN, NO₂, NHC(O)CH₃,C₁₋₄alkyl, F, Cl, I or Br; Y is H, C₁₋₄alkyl, CF₃, CN, NO₂, F, Cl, I orBr; Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₄alkenyl, C₂₋₄alkynyl,C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] orO—[CH₂CH₂N(CH₃)₂]; R₁ is H, OH, F, Cl, Br or I; R₂ is H, benzylsubstituted with R₆, (CH₂)₂—O-p-cyanophenyl, CH₂—O-p-cyanophenyl, orCH═CH—O-p-cyanophenyl; R₃ is H C₃₋₄alkyl, halide, CN or NO₂; R′ is NH₂,OH or CH₃; and R₆ is CN, NO₂, NHC(O)CH₃ or halide.
 24. The compound ofclaim 23, wherein X₄ is O.
 25. The compound of claim 24, wherein A isCH₂OH or CN.
 26. (canceled)
 27. The compound of claim 23, wherein Q isCN, R₁ and R₂ are H.
 28. The compound of claim 23, wherein Q is CN, Z isCN, Y is CF₃, and R₁, R₂ and R₃ is H.
 29. The compound of claim 23,represented by the following structure:


30. The compound of claim 23, wherein said compound is represented bythe structure of formula XIII:


31. The compound of claim 1, wherein said compound is represented by thestructure of formula XVII:

wherein X₄ is S(O)[═CHCH₂N(CH₃)₂], C(OH)[CH₂CH₂N(CH₃)₂],C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂], NO[CH₂CH₂N(CH₃)₂]; Qis H, CN, OH, NO₂, halide, C₂₋₆alkenyl, C₂alkynyl, C(O)CH₂NH₂,C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂, NH(C₁₋₄alkyl),NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂. NHCO(C₁₋₄alkyl),NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₄₋₈cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(CH₃)₂]; Z is H, CN, NO₂,NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br, and Y is H, C₁₋₄alkyl CF₃, CN,NO₂, F, Cl, I or Br;
 32. The compound of claim 31, wherein Q is F or CN.33. (canceled)
 34. (canceled)
 35. The compound of claim 31, wherein Q isCN, Z is CN and Y is CF₃.
 36. The compound of claim 1, wherein saidcompound is represented by the structure of formula XIX:

wherein X is C or N; W is C or N X₂ is C₁₋₄alkylene, SO₂, C(O),CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄alkyl), CH(NH₂), CH(OH), CH(C₁₋₄ haloalkyl),a bond; X₃ is C₁₋₄ alkylene, NH, N, CH(OH) or a bond; X₄ is O, S, SO,C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO, C₁₋₄alkylene,C(OH)[CH₂CH₂N(CH₃)₂], C[CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl),N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond; A is H OH, SH, NH₂,C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl),CH₂CN, CH₂N₃, CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,C(O)O(C₁₋₄ alkyl), C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ orC(O)CH═CH₂; Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; Y isH, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br; Q is H, CN, OH, NO₂, CF₃halide, C₂₋₆alkenyl, C₂₋₆alkynyl, C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl),C(O)N(C₁₋₄alkyl)₂, C(O)NH₂, NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl),CH₂C(O)NH₂, NHC(O)NH₂, NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl),O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₄₋₈cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(CH₃)₂]; R₁ is R OH, F, C,Br or I; R₂ is H, benzyl substituted with R₆, (CH₂—O-p-cyanophenyl,CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl; R′ is NH₂, OH or CH₃; andR₆ is CN, NO₂, NHC(O)CH₃ or halide; wherein if X is C, X₁ is NH, X₂ isC(O), R is OH, A is alkyl, X₃ is a bond or CH₂ and X₄ is bond Or CH₂, R₁and R₂ are H, then Q is not H or halogen.
 37. The compound of claim 36,wherein X₂ is CH₂ or C(O).
 38. (canceled)
 39. The compound of claim 36,wherein X₃ is CH₂.
 40. The compound of claim 36, wherein X₄ is O. 41.The compound of claim 36, represented by the following structure:


42. The compound of claim 1, wherein P is formula II, and X₂ and R₃together with X₁, form a ring, which is a saturated or unsaturated,substituted or unsubstituted 5- or 6-membered ring.
 43. The compound ofclaim 42, wherein said saturated or unsaturated, substituted orunsubstituted 5- or 6-membered ring is pyrrolidine, pyrrole, morpholine,piperidine-4-one, or piperidine.
 44. The compound of claim 42, whereinsaid compound is represented by the structure of formula XX:

wherein X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl),N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond; A is H, OH, SH, NH₂,C₁₋₄alkyl, CHF₂, CH₂F, CF₃, CN, CH₂OH, CH₂O(C₁₋₄alkyl), CH₂O(C₁₋₄acyl),CH₂CN, CH₂N₃, CH₂NCS, CHO, C(O)O(C₁₋₄alkyl), CONHR′, C(O)N(R′)₂,C(O)O(C₁₋₄alkyl), C(O)R′, CH₂CF₃, CF₂CF₃, CH₂OR′CH₂C(O)CH═CH₂ orC(O)CH═CH₂; Z is H, CN, NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; Y isH, C₁₋₄alkyl, CF₃, NO₂, CN, F, Cl, I or Br; Q is H, CN, OH, CF₃, NO₂,halide, C₂₋₉alkenyl, C₂₋₄alkynyl, C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl),C(O)N(C₁₋₄alkyl)₂, C(O)NH₂, NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl),CH₂C(O)NH₂, NHC(O)NH₂, NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl),O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₄₋₈cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(CH₃)₂]; R₁ is H, OH, F,Cl, Br or I; R₂ is H, benzyl substituted with R₆, (CH₂)₂—O-cyanophenyl,CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl; R′ is NH₂, OH or CH₃; andR₆ is CN, NO₂, NHC(O)CH₃ or halide.
 45. (canceled)
 46. (canceled) 47.(canceled)
 48. (canceled)
 49. (canceled)
 50. The compound of claim 44,wherein A is CH₃, X₄ is O, Z is CN, Q is CN, R₁ and R₂ are H and Y isCF₃.
 51. The compound of claim 44, represented by the followingstructure:


52. The compound of claim 42, wherein said compound is represented bythe structure of formula XXI:


53. (canceled)
 54. (canceled)
 55. (canceled)
 56. (canceled)
 57. Thecompound of claim 52, wherein A is CH₃, X₄ is O, Z is CN, Q is CN, R₁and R₂ are H, and Y is CF₃.
 58. The compound of claim 52, represented bythe following structure:


59. The compound of claim 42, wherein said compound is represented bythe structure of formula XXII:

wherein A, Z, Y, X₄, Q, R₁ and R₂ are as described in formula XX, R₇ isH or oxo and R₈ is H or ═CH₂.
 60. (canceled)
 61. (canceled)
 62. Thecompound of claim 58, wherein R₇ is ═CH₂ or H and R₈ is oxo or H. 63.(canceled)
 64. (canceled)
 65. (canceled)
 66. The compound of claim 58,wherein A is CH₃, X₄ is O, Z is CN, Q is CN, R₁ and R₂ are H, and Y isCF₃.
 67. The compound of claim 58, represented by the followingstructure:


68. The compound of claim 1, wherein P is formula II, and X₃ and X₁together with X₂ and X₅ to which X₁ and X₃ are attached form a saturatedor unsaturated, substituted or unsubstituted 5- or 6-membered ring; 69.The compound of claim 68, wherein said 5 or 6 saturated or unsaturated,substituted or unsubstituted membered ring is piperazine,piperazine-2,6-dione, piperidine, pyrrolidine, cyclohexanone,cyclohexane, cyclohexene, cyclopentanone, cyclopentane, cyclopentene,succinimide, oxazolidine, oxazolidinedione, oxazolidinone. 70.(canceled)
 71. (canceled)
 72. (canceled)
 73. (canceled)
 74. (canceled)75. (canceled)
 76. (canceled)
 77. (canceled)
 78. (canceled) 79.(canceled)
 80. The compound of claim 1, wherein P is formula II, and X₃and X₅ form a saturated or unsaturated, substituted or unsubstituted 5-or 6-membered ring,
 81. The compound of claim 80, wherein said saturatedor unsaturated, substituted or unsubstituted 5- or 6-membered ring istetrahydrofuran, pyrrolidine, piperidine, cyclohexanone, cyclohexane,cyclohexene, cyclohexenone, cyclopentanone, cyclopentenone,cyclopentane, cyclopentene, succinimide, oxazolidine, oxazolidinedione,oxazolidinone.
 82. The compound of claim 80, wherein said compound isrepresented by the structure of formula XXXIV:

X is C or N; W is C or N X₂ is C₁₋₄alkylene, SO₂, C(O),CH—[CH₂—(C₄₋₈ring)], CH(C₁₋₄ alkyl), CH(NH₂). CH(OH), CH(C₁₋₄haloalkyl),a bond; X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂], SO₂, NH, NHR′, NO,C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂], PO(C₁₋₄alkyl),N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond; Z is H, CN, NO₂, NHC(O)CH₃,C₁₋₄alkyl, F, Cl, I or Br; Y is C₁₋₄alkyl, CF₃ NO₂, CN, F, Cl, I or Br;Q is H, CN, OH, NO₂, CF₃, halide, C₂₋₆alkenyl, C₂₋₄alkynyl, C(O)CH₂NH₂,C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂, NH(C₁₋₄alkyl),NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂, NHCO(C₁₋₄alkyl),NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂], O—[CH₂CH₂(C₄₋₈cycloalkyl)],O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] or O—[CH₂CH₂N(C₃)₂]; R₁ is H, OH, F,Cl, Br or I; R₂ is H benzyl substituted with R₆, (CH₂)₂—O-p-cyanophenyl,CH₂—O-p-cyanophenyl, or CH═CH—O-p-cyanophenyl; R₃ is H, C₁₋₄alkyl,halide, CN or NO₂; R′ is NH₂, OH or CH₃; and R₆ is CN, NO₂, NHC(O)CH₃ orhalide.
 83. The compound of claim 82, wherein X₄ is O.
 84. The compoundof claim 82, wherein Q is CN.
 85. The compound of claim 82, wherein X₂is CH₂ or C(O).
 86. The compound of claim 82, wherein X₂ is C(O). 87.The compound of claim 82, wherein Z is CN and Y is CF₃.
 88. The compoundof claim 82, wherein said compound is represented by the structure offormula XXXV:


89. The compound of claim 82, wherein said compound is represented bythe structure of formula XXXVI:


90. (canceled)
 91. (canceled)
 92. (canceled)
 93. (canceled) 94.(canceled)
 95. (canceled)
 96. (canceled)
 97. (canceled)
 98. (canceled)99. (canceled)
 100. (canceled)
 101. (canceled)
 102. The compound ofclaim 1, wherein P is formula II, and X₁ and X₅ together with X₂ towhich X₁ and X₅ are attached form a saturated or unsaturated,substituted or unsubstituted S— or 6membered ring; wherein if P isformula III, X is C, X₃ is CH₂, X₄ is O, or NH; R₁, R₂ and R₃ are H, andX₅ and X₁ forms a 5 membered ring, an oxazolidine-2-one then Q is nothalogen, or H;
 103. The compound of claim 102 wherein said 5 or 6saturated or unsaturated, substituted or unsubstituted membered ring ispyrrolidine, piperidine, morpholine, succinimide, oxazolidine,oxazolidinedione, oxazolidinone
 104. The compound of claim 102 whereinsaid compound is represented by the structure of formula XXXIX:

wherein: X is C or N; W is C or N; G is O, NH, NC₁₋₄alkyl NC₁₋₄acyl, S,C₁₋₄C₁₋₄alkyl, CHC₁₋₄acyl, C(C₁₋₄acyl)₂, C(C₁₋₄alkyl)₂ or (CH₂)_(n),where n is 1-3; T is S or O; X₄ is O, S, SO, C(O), S(O)[═CHCH₂N(CH₃)₂],SO₂, NH, NHR′, NO, C₁₋₄alkylene, C(OH)[CH₂CH₂N(CH₃)₂], C[═CHCH₂N(CH₃)₂],PO(C₁₋₄alkyl), N[CH₂CH₂N(CH₃)₂]NO[CH₂CH₂N(CH₃)₂] or a bond; Z is HI, CN,NO₂, NHC(O)CH₃, C₁₋₄alkyl, F, Cl, I or Br; Y is H, C₁₋₄alkyl, CF, NO₂,CN, F, Cl, I or Br; Q is H, CN, OH, CF₃, NO₂, halide, C₂₋₆alkenyl,C₂₋₆alkynyl, C(O)CH₂NH₂, C(O)NH(C₁₋₄alkyl), C(O)N(C₁₋₄alkyl)₂, C(O)NH₂,NH(C₁₋₄alkyl), NHC(O)NH(C₁₋₄alkyl), CH₂C(O)NH₂, NHC(O)NH₂,NHCO(C₁₋₄alkyl), NHSO₂(C₁₋₄alkyl), O—[CH₂CH₂CH(CH₃)₂],O—[CH₂CH₂(C₄₋₈cycloalkyl)], O—[CH₂CH₂(C₄₋₈heterocycloalkyl)] orO—[CH₂CH₂N(CH₃)₂]; R is H, OH, C₁₋₄alkyl, CF₃, CH₂OH, O(C₁₋₄alkyl) orO(C₁₋₄acyl); R₁ is H, OH, F, Cl, Br or I; R₂ is H, benzyl substitutedwith R₆, (CH₂)₂—O-p-cyanophenyl, CH₂—O-p-cyanophenyl, orCH═CH—O-p-cyanophenyl; R₃ is H, C₁₋₄alkyl, halide, CN or NO₂; R′ is NH₂,O or CH₃; and R₆ is CN, NO₂, NHC(O)CH₃ or halide.
 105. The compound ofclaim 104, wherein said compound is represented by the structure offormula XLV:

wherein X₄ is as described above for compound XXXIV.
 106. The compoundof claim 105, wherein X₄ is O.
 107. The compound of claim 102 whereinsaid compound is represented by the structure of formula XLII:

wherein: X, X₄, R, R₁, R₂, R₃, Z, Y and Q are as described above forcompound XXXIV; wherein if X is C, X₄ is O, N, or S, R₁, R₂ and R₃ are Hand R is H then Q is not halogen, H or CN;
 108. (canceled) 109.(canceled)
 110. (canceled)
 111. (canceled)
 112. (canceled) 113.(canceled)
 114. A pharmaceutical composition comprising the compound ofclaim 1, and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, N-oxide, hydrate or any combinationthereof, and a suitable carrier or diluent.
 115. A pharmaceuticalcomposition comprising an effective amount of the compound of claim 1,and/or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal N-oxide, hydrate or any combination thereof; and apharmaceutically acceptable carrier, diluent or salt.
 116. A method ofcontraception in a male subject, comprising the step of administering tosaid subject the compound of claim 1 and/or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal, N-oxide, hydrate orany combination thereof in an amount effective to suppress spermproduction in said subject, thereby effecting contraception in saidsubject.
 117. A method of hormone therapy comprising the step ofcontacting an androgen receptor of a subject with the compound of claim1 and/or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal, N-oxide, hydrate or any combination thereof, in anamount effective to effect a change in an androgen-dependent condition.118. A method of treating and/or delaying the progression of prostatecancer in a subject suffering from prostate cancer, comprising the stepof administering to said subject the compound of claim 1 and/or isomer,pharmaceutically acceptable salt, pharmaceutical product, crystalN-oxide, hydrate or any combination thereof, in an amount effective totreat prostate cancer in said subject.
 119. (canceled)
 120. A method oftreating a bone-related disorder in a subject, or increasing a bone massin a subject, promoting bone formation in a subject, comprising the stepof administering to said subject the compound of claim 1 or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,hydrate, N-oxide or any combination thereof, in an amount effective totreat said bone-related disorder.
 121. The method of claim 120, whereinsaid subject suffers from osteoporosis, osteopenia, increased boneresorption, bone fracture, bone frailty, loss of bone mineral density(BMD), or any combination thereof.
 122. The method of claim 120, whereinsaid method increases the strength of a bone of said subject.
 123. Themethod of claim 120, wherein said compound stimulates or enhancesosteoblastogenesis.
 124. The method of claim 120, wherein said compoundinhibits osteoclast proliferation.
 125. A method of treating, reducingthe incidence of, delaying progression of, reducing the severity of, oralleviating symptoms associated with a muscle wasting disorder in asubject, comprising the step of administering to said subject thecompound of claim 1 or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal, hydrate, N-oxide or any combinationthereof, in an amount effective to treat said muscle wasting disorder insaid subject.
 126. (canceled)
 127. (canceled)
 128. (canceled) 129.(canceled)
 130. A method of treating, reducing the severity of, reducingthe incidence of, delaying the onset of, or reducing pathogenesis ofdiabetes and/or glucose intolerance in a human subject, comprising thestep of administering to said subject a compound of claim 1 and/or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof.
 131. (canceled)132. A method of treating, reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis ofhyperinsulinemia and/or insulin resistance in a human subject,comprising the step of administering to said subject a compound of claim1 and/or its isomer, pharmaceutically acceptable salt, pharmaceuticalproduct, crystal N-oxide, hydrate or any combination thereof. 133.(canceled)
 134. A method of treating, reducing the severity of, reducingthe incidence of, delaying the onset of, or reducing pathogenesis ofdiseases associated with diabetes comprising the step of administeringto said subject a compound of claim 1 and/or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof.
 135. A method of treating,reducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of fatty liver conditions in a humansubject comprising the step of administering to said subject a compoundof claim 1 and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal N-oxide, hydrate or any combinationthereof.
 136. A method of treating, reducing the severity of, reducingthe incidence of, delaying the onset of, or reducing pathogenesis ofcardiovascular disease in a human subject, comprising the step ofadministering to said subject a compound of claim 1 and/or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof.
 137. A method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of cachexia in a subject, comprising thestep of administering to said subject a compound of claim 1 and/or itsisomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof.
 138. (canceled)139. A method of treating reducing the severity of, reducing theincidence of, delaying the onset of, or reducing pathogenesis ofrheumatoid arthritis in a subject, comprising the step of administeringto said subject a compound of claim 1 and/or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof.
 140. A method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of chronic kidney disease and/or end-stagerenal disease in a subject, comprising the step of administering to saidsubject a compound of claim 1 and/or its isomer, pharmaceuticallyacceptable salt, pharmaceutical product, crystal N-oxide, hydrate or anycombination thereof.
 141. (canceled)
 142. A method of treating reducingthe severity of, reducing the incidence of, delaying the onset of orreducing pathogenesis of frailty in a subject, comprising the step ofadministering to said subject a compound of claim 1 and/or its isomer,pharmaceutically acceptable salt, pharmaceutical product, crystal,N-oxide, hydrate or any combination thereof.
 143. A method of treatingreducing the severity of, reducing the incidence of, delaying the onsetof, or reducing pathogenesis of hypogonadism in a subject, comprisingthe step of administering to said subject a compound of claim 1 and/orits isomer, pharmaceutically acceptable salt, pharmaceutical product,crystal, N-oxide, hydrate or any combination thereof.
 144. A method oftreating reducing the severity of, reducing the incidence of, delayingthe onset of, or reducing pathogenesis of age-related functional declinein a subject, comprising the step of administering to said subject acompound of claim 1 and/or its isomer, pharmaceutically acceptable salt,pharmaceutical product, crystal N-oxide hydrate or any combinationthereof.